Prevalence of lipodystrophy and risk factors for dyslipidemia in HIV-infected children in Brazil

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The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Original

Article

Prevalence

of

lipodystrophy

and

risk

factors

for

dyslipidemia

in

HIV-infected

children

in

Brazil

Luanda

Papi

a

_,

_Ana

_Carolina

_G.B.

_Menezes

b

_,

_Hélio

_Rocha

c

_,

_Thalita

_F.

_Abreu

c

_,

Ricardo

Hugo

de

Oliveira

c

_,

_Ana

_Cristina

_C.

_Frota

c

_,

Lucia

de

A. Evangelista

c

_,

_Cristina

_B.

_Hofer

a,∗

a_Preventive_Medicine,_Universidade_Federal_do_Rio_de_Janeiro_(UFRJ),_Rio_de_Janeiro,_RJ,_Brazil b_Universidade_Federal_do_Rio_de_Janeiro_(UFRJ),_Rio_de_Janeiro,_RJ,_Brazil

c_Department_of_Pediatrics,_Universidade_Federal_do_Rio_de_Janeiro_(UFRJ),_Rio_de_Janeiro,_RJ,_Brazil

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Articlehistory:

Received10October2013

Accepted10December2013

Availableonline30April2014

Keywords: HIV Lipodystrophy Dyslipidemia Children

a

b

s

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Theaimofpresentstudywastodescribethefrequencyoflipodystrophysyndrome

asso-ciatedwithHIV(LSHIV)andfactorsassociatedwithdyslipidemiainBrazilianHIVinfected

children.

HIVinfectedchildrenonantiretroviraltreatmentwereevaluated(nutritionalassessment,

physicalexamination,andlaboratorytests)inthiscross-sectionalstudy.Univariate

anal-ysiswasperformedusingMann–Whitneytestor Fisher’sexact testfollowedbylogistic

regressionanalysis.Presenceofdyslipidemia(fastingcholesterol>200mg/dlortriglycerides

>130mg/dl)wasthedependentvariable.

90 children wereenrolled. The mean age was10.6 years (3–16 years), and 52 (58%)

werefemale. LSHIV was detected in 46 children (51%). Factors independently

associ-atedwithdyslipidemiawere:lowintakeofvegetables/fruits(OR=3.47,95%CI=1.04–11.55),

currentuseoflopinavir/ritonavir(OR=2.91,95%CI=1.11–7.67).Inconclusion,LSHIVwas

frequentlyobserved;inadequatedietaryintakeofsugarsandfats,aswellascurrentuseof

lopinavir/ritonavirwasassociatedwithdyslipidemia.

Introduction

Antiretroviral therapy(ARV) has changedhuman

immuno-deﬁciencyvirus (HIV) infectionfrom anear-uniformly fatal

diseaseintoachronic,manageableillness.Beforethe

avail-abilityofhighlyactiveantiretroviraltherapy(HAART),5–10%

∗ _{Corresponding}_author_at:_Rua_Bruno_Lobo,₅₀_–_Ilha_do_Fundão,_21941-612,_Rio_de_Janeiro,_Brazil.

E-mailaddress:cbhofer@hucff.ufrj.br(C.B.Hofer).

ofinfectedchildrensurvivedformorethanthreeyearsafter

their serologic diagnosis. Presently, the mortality rate has

decreased70%.1_Children_who_survived_HIV_disease_and_AIDS

are anewchallengetoHIV/AIDS carestandards, sincethis

is the ﬁrst generation of childrenwho had the chance to

useHAART.2_One_important_challenge_are_the_adverse_events

associated withHAART, as theyare described inadultsas

http://dx.doi.org/10.1016/j.bjid.2013.12.007

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wellasinchildren.Thelipodystrophysyndrome(LSHIV),the

redistributionofbodyfat(increasedofcentripetalfat–

lipo-hypertrophyand/orreductionofperipheralfat–lipoatrophy)

and/ormetabolicchangesrelatedtolipidsproﬁle

(dyslipide-mia),andglucoseintolerance,isoneexampleoftheseadverse

events.3–5 _Another_important_issue_is_that_HIV_infected

chil-drenandtheircaregiversmustalsodealwithotherchallenges,

relatedtotheprevailingsocioeconomicconditionsin

develop-ingcountries,suchasnutritiondeprivation,poornutritional

quality,orlackofregularphysicalactivities.6

Theaimofthisstudy wastodescribetheprevalenceof

LSHIVandassessfactorsassociatedwithdyslipidemiainHIV

infectedchildrentreatedwithARV, inadevelopingcountry

setting,consideringtheirnutritionroutine.

Materials

and

methods

Thisisa cross-sectionalstudy conductedatthe HIV clinic

ofInstitutode PuericulturaePediatriaMartagãoGesteira, a

tertiaryuniversitypediatrichospitalafﬁliatedtothe

Univer-sidadeFederaldoRiodeJaneiro(IPPMG–UFRJ),fromOctober

2007toJanuary2009.Childrenwereincludediftheyweretwo

ormoreyearsold,HIVinfected(conﬁrmedbytwodifferent

serologicaltestsafter18monthsofage),andoncontinuous

ARVforatleastthelastthreemonthspriortotheinterview.

Childrenwereexcludediftheyhadatthetimeof

assess-ment any of the following: severe infection, opportunistic

orbacterialinfections,neoplasticdisease,severe

encephalo-pathy,wastingsyndrome,orothermetabolicdisorders(such

asdiabetesandinbornerrorsofmetabolism).

TheLSHIVwasdeﬁnedasredistributionofbodyfatthrough

peripherallipoatrophy,centripetallipohypertrophyormixed

form– presenceof the two typesof redistribution,and/or

alsothepresenceoflaboratoryabnormalities(dyslipidemia),

basedonthecriteriadeﬁnedbytheEuropeanPediatricGroup

lipodystrophy.4 _Dyslipidemia _was _deﬁned_as_serum

choles-terol≥200mg/dlandserumtriglyceride≥130mg/dl,after12h

fasting.Data werecollectedduringtheinterview andsame

pediatrician(LP)didallphysicalexaminations.Height,weight,

triceps,subscapular,andbrachialskinfolds,aswellaswaist

circumferenceweremeasured.Waistandarmcircumference

were measured with ordinary tape measure. Sub-scapular

and arm skin folds were measured with Langer

adipome-ter,properlycalibrated.Allmeasuresweretakenthreetimes,

and a mean of them was used. Collected data were

com-paredwiththeNationalCenterforHealthStatisticsstandard

growthcurve7_and _transformed_into_z-scores_using_the

for-mula: z-score=(observed value−mean)/standard deviation.

Anthropometricdatawerecomparedwiththetablessuitable

forage.8 _Based_on_this _{anthropometric} _data, _patients_were

classiﬁed as presenting peripheral lipoatrophy, centripetal

lipohypertrophyormixedformofLSHIV.Patientswere

classi-ﬁedaccordingtoTannercurve,bythepediatrician(LP).

Laboratorydataonfasting cholesterol,triglycerides,

glu-cose,CD4+Tlymphocytesandviralloadwerealsocollected.

Afoodassessmentsurveywasconductedassessingthe

48-hfoodrecall.Resultswereanalyzedaccordingtoqualityand

quantityofeachfoodgroup.Itwasconsideredinadequateif

foodintakewasexcessiveandofpoorqualityand/orwhenit

wasbelowtherecommendedforeachparticularfoodgroup.9

Antiretroviraltherapy(ARV),butthezidovudinesyrupused

forHIVverticaltransmissionprevention,wasdeﬁnedasthe

continuoususeofanyantiretroviralmedication.

Food deprivation was considered when the patient was

starvinganddidnothavefoodaccessenoughhis/herfor

well-beingforaweekormoreduringtheirlives(excludingdietary

recommendations).

Thedependent variable was deﬁnedas the presenceor

absence ofdyslipidemiain children.Independentvariables

weregender,age,ageatHIVdiagnosis,lengthofHAARTuse,

CD4+Tlymphocytespercentcells,andviralloadatthetimeof

theinterview.Socioeconomicstatusandnutritionalvariables

were alsoevaluated: number ofminimum Brazilian wages

per capita,history offood deprivation(whenthechild had

nofoodshortagesduetopoverty),inadequateintake(overor

lackthereof)offoodgroups,treatmentcompliance(deﬁned

asself-reportadherencetoatleast95%ofprescribeddosesof

ARV,threedayspriortheinterview),physicalactivity(atleast

30minper day,atleastthreetimesaweekofanyphysical

activity).

Statisticalanalysis:theinformationobtainedinthe

ques-tionnaires were stored in a database using Access 2007®

software. Subsequently, the distribution of all continuous

variables was studied. The frequencyofall the categorical

variables was described and univariate analysis of

con-tinuous variables was performed using Student’s t-test or

Mann–Whitneytestifthevariabledidnothavenormal

dis-tribution. Univariate analysis of categorical variables was

performedusingtheFisherexacttestfollowedby

multivari-ate logistic regression analysis. The independentvariables

selectedtobeincludedintheﬁnalmodelwerethosethatin

univariateanalysispresentedwithp-value<0.15.Statistical

analysiswasperformedusingthestatisticalpackageSTATA

version9.0,Texas,USA.

Ethicalconsiderations:thisstudywasapprovedbyIPPMG–

EthicalCommittee.

Results

Ninety patients were enrolled. The mean age was 127.3

months, and 52 children were female. Among the female

group, 16 had history ofmenarche. Themean age of

chil-drenwhentheywereﬁrstdiagnosedasHIVinfectedwere37

months.

Amongthe legalguardiansofthose children,58 (64.4%)

wereilliterateorhadlessthaneightyearsofeducation.

AllchildrenwereusingARVforatleastthreemonths,32

wereintheirﬁrstARVregimen,27wereinsecondARV

reg-imen,and31hadexperiencedthreeormoreARVregimens.

Proteaseinhibitor(PI)basedregimenwasthecurrentARV

regi-menof47children(43onlopinavir/ritonavir),whereas33were

on non-nucleoside reverse transcriptase inhibitors (NNRTI)

basedregimens,and10patientswerecurrentlyusing

nucleo-sidereversetranscriptaseinhibitors(NRTI)basedregimens.

AccordingtotheEuropeanPediatricGrouplipodystrophy

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16 with clinical changes only

33 with laboratorial changes (15 with only laboratorial changes and 15 with laboratorial and clinical changes)

44 without SLHIV

Clinical characteristics

10 with fat loss in the face 7 with zygomatic prominence

16 with fat loss in the limbs 7 with prominence of veins 2 with fat loss in the buttocks

1 with looseness in the buttocks 20 lipoatrophy

(2 only lipoatrophy)

29 lipohipertrophy (11 only lipohipertrophy)

18 with both clinical manifestation 29 with fat accumulation in

abdomen

6 with breast enlargement 15 with only laboratorial

changes 90 children 46 with SLHIV

10 with high cholesterol

5 with clinical changes 20 with high triglycerides

7 with high cholesterol 3 with changes of cholesterol and triglycerides 2 with clinical changes Laboratorial characteristics

Fig.1–DistributionofchildrenaccordingtoclinicalandlaboratorycharacteristicsofSLHIV.

Nochildrenpresentedhyperglycemia.Themeancholesterol

was153.2mg/dlandthemeantriglyceridewas111.4mg/dl.

Overall mean body mass index (BMI) was 16.6 (z-score

−0.34),17.1forthegroupwithoutLSHIVand15.4forthegroup

withLSHIV(p=0.01).

In Table 1 shows demographic, clinical, and laboratory

characteristicsaccordingtothepresenceorabsenceofLSHIV

Demographiccharacteristics (income), clinical presentation

(categoryCevent),laboratorydata(nadirCD4+lymphocytes),

useofARV(lopinavir/ritonavir),andnutritionalhistorywere

associatedwithLSHIV.

CD4+ T lymphocytes varied from 45 to 2300cells/mm3

(3–50%),andviralloadatthemomentoftheinterviewvaried

fromundetectableto80,4000copies/mL.Allvariableswith

p-value<0.15wereincludedinthemultivariateanalysis,except

BMI.Table2showstheresultofthemultivariateanalysis.

Discussion

Among90childrenonARV,51%(46)wereclassiﬁedashaving

LSHIV;22%presentedlipoatrophyand 32%lipohypertrophy.

Theproportionofchildrenaffectedbythissyndromeranged

from20to50%,accordingtostudiesthatevaluateddifferent

populations.10–14 _In_studies _of_adult_groups,_the _prevalence

ofLSHIVvariedfrom15to50%.15_An_European_study_of₄₂₆

childrenfounda 42% prevalenceofclinical manifestations

ofLSHIV.14 In astudy involving 364Ugandan children,the

prevalencewaslower:27%presentedclinicalmanifestations

and34%laboratoryabnormalities.Glucosemetabolism

abnor-malitieswere notobserved.16 Werneretal.inastudyof30

BrazilianchildrenonARV,found88.3%withdyslipidemia

(lab-oratoryabnormality)andonly13.9%withabnormalbodyfat

distribution.17

Sinceallclinicaldiagnoseswerepronetoobserverbias,i.e.

evenmeasuringcircumferencesandskinfolds,thediagnosis

ofLSHIVisultimatelybasedoninvestigatorimpression,and

hence westudiedriskfactorsassociatedwithdyslipidemia,

consideringnutritionalhistoryinourpopulation.

Amongtheriskfactorsdescribedintheliterature,

dysli-pidemiawasassociatedwitholderage,higherTannerscores,

and use ofARV(such asstavudine,lopinavir/ritonavir, and

NNRTIs),whiteethnicity,orhigherviralload.11,14,16,18–20_In_our

study,theriskfactorsindependentlyassociatedwith

dyslipid-emiawerelowintakeofvegetables/fruitsandcurrentuseof

lopinavir/ritonavir.

Arpadi et al. observed signiﬁcant associations between

worse virologicalandimmunological statusatthebaseline

visit and the presence of changes consistent with LSHIV

ina groupofchildren.18 _A_study _of_the _European_Pediatric

GroupofLipodystrophydemonstratedasigniﬁcant

relation-shipbetweenchildrendiagnosedasclinicalcategoryC(CDC)

withlower CD4+Tlymphocytesandonsetofchanges

con-sistent with LSHIV.4 _A _Thai _pediatric _study _also _described

an association between the baseline C clinical category

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Table1–Demographic,clinical,andlaboratorycharacteristicsofthepatients. PatientswithLSHIVb

(n=46–51%) Patientswithout LSHIV(n=44–49%) ORd _p-Value Gender–female 27/46(59%) 25/44(57%) 1.08 0.86 HIV-verticallyinfected 44/46(96%) 40/44(91%) 0.16 0.51 Race–Caucasian 16/46(35%) 11/44(25%) 0.62 0.31

Admittedtothehospitalinthelastyear 10/46(22%) 4/44(9%) 2.77 0.10a

Regularphysicalactivity 11/46(24%) 10/44(23%) 1.06 0.89

Historyoffooddeprivation 13/46(28%) 9/44(20%) 1.53 0.39

Income–perperson(minimumBraziliansalarywages(mean) 0.56 0.83 0.04a

Birthweight(mean–g) 2586 2329 0.42

Age(attheinterview),months(mean–months) 121.8 133.1 0.19

ClinicalclassiﬁcationC(CDC) 23/46(50%) 15/44(34%) 1.93 0.07

Onanyproteaseinhibitor 27/46(59%) 20/44(45%) 1.71 0.21

OnLPV/rc _27/46_(59%) _16/44_(36%) _2.49 _0.03a

TimeonthecurrentARVregimen(mean–months) 25.5 28.7 0.53

100%adherence,3dayspriortotheinterview 17/46(37%) 11/44(25%) 1.76 0.22

Inadequateintakeofsugarsandfat 23/46(50%) 10/44(23%) 3.40 <0.01a

Inadequateintakeofmilkanddairyproducts 16/46(35%) 10/44(23%) 1.81 0.21

Inadequateintakeofprotein 12/46(26%) 8/44(18%) 1.59 0.37

Inadequateintakeofvegetables/fruits 40/46(87%) 29/44(67%) 3.40 0.02a

Inadequateintakeofcereals 9/46(20%) 4/44(9%) 2.43 0.18

Nadir%CD4+Tcells(mean) 15.17 19.70 0.06a

Actual%CD4+Tcells(mean) 25.67 25.93 0.81

Baselineviralload–log(mean) 5.84 5.79 0.80

Currentviralload–log(mean) 4.47 3.74 0.19

CurrentASTe_–_units/mL_(mean) ₃₃ ₂₈ _0.07a

CurrentALTf_–_units/mL_(mean) ₂₀ ₁₈ _0.54

a _Variables_included_in_multivariate_analysis. b _LSHIV:_{lipodystrophy}_syndrome_associated_with_HIV. c _{Lopinavir/ritonavir.}

d _Odds_ratio.

e _Aspartate_{aminotransferase.} f _Alanine_{aminotransferase.}

CD4+T lymphocytes.21 _In_our _study,_we _did_not _observe _a

relationshipbetweendyslipidemiaandimmunosuppression,

probablybecausethisassociationisrelatedwithclinical

man-ifestationsoftheLSHIVmorethanlaboratoryabnormalities.

Flintetal.suggestedthatbothtreatmentwithantiretroviral

drugsandsomechronicinﬂammatoryresponsetoHIV

stim-ulatedthehomeostaticresponsetostressatthecellularlevel,

leadingtoadverseeffectsontheadipocytesmetabolism.This

processleadstoacycleofpathologicallipotoxicity,

lipoatro-phyand,consequently,thephenotypeoffatdistributionwith

highwaist–hipratio,andofcoursethemoresevereHIVdisease

thechildhad,theworsethehomeostaticresponsetostress

atthecellularleveltheywouldpresent.22_Another_important

issuepossiblyassociatedwiththeinﬂammatoryresponsewas

thepositiveassociationbetweenaspartateaminotransferase

(AST)andthepresenceofLSHIV.ASTisacomponentofthe

ASTplateletratioindex(APRI).Thisindex(AST/platelets)is

associatedwithliverﬁbrosisamongHIVinfectedpatientswith

andwithoutotherviralhepatitis23_patients,_and_a_possible

eti-ologyforthisﬁbrosisistheinﬂammatorydisorderassociated

Table2–Multivariateanalysis–factorsassociatedwithLSHIV.a

ORc _95%CId _p-Value

Income–perperson(minimumBrazilianwage)salarywages(mean) 0.96 0.77–1.21 0.74

Nadir%CD4+percell 0.96 0.92–1.00 0.08

Inadequateintakeofvegetables/fruits 1.81 0.56–5.84 0.32

Inadequateintakeofsugarsandfat 3.05 1.10–8.46 0.03

OnLPV/rb _2.51 _0.94–6.75 _0.06

Admittedtothehospitalinthelastyear 1.87 0.45–7.74 0.39

CurrentASTe_–_per_Unit/mL _1.05 _1.00–1.11 _0.05

a _LSHIV:_{lipodystrophy}_syndrome_associated_with_HIV. b _{Lopinavir/ritonavir.}

c _Odds_ratio.

d _95%_conﬁdence_interval. e _Aspartate_{aminotransferase.}

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withHIV.TheincreasedASTobservedintheunivariate

analy-siswouldalsobeasurrogatemarkeroffattyhepaticsteatosis,

morefrequentlydescribedinobesechildren.However,ifthis

wasthecase,thealanineaminotransferaseshouldhavealso

beenelevated,whichwasnotthecase.24_Another

hypothe-sisforthisﬁndingisthatASTisincreasedduetotheuseof

ARV;Ottopetal.studied230HIVinfectedadultsinCameroon,

andpatientswhowereonARVhadhigherASTlevelswhen

comparedwiththosewithoutARV.25

Althoughinterventionstoavoidandimprovedyslipidemia

werefrequentlybasedonimprovingthequalityofdiet,26_few

studiesevaluatedthedietamongLSHIVpatients,andnonein

children,includingchildrenfromdevelopingcountries.

The analysis of dietary survey was carried out

accord-ing tospeciﬁcfoodgroups andwas consideredinadequate

whenaboveorbelowtherecommendeddailyamountforthe

age-speciﬁcchildren.Individually,weobservedthatlower

veg-etablesand sugar intakewere signiﬁcantlyassociatedwith

LSHIV.These datasupportthehypothesis that,despitethe

absenceoffooddeprivation,thequalityofnutritionwasfar

belowtherecommendedlevels.Suchchildrenwithpoor

nutri-tionhavegreaterchanceofdevelopingdyslipidemia.Areview

byAlmeidaetal.,of20dietaryinterventionstudiesinadults,

concludedthatchangesinlifestyle,dietandphysical

activ-itywere always recommendedas theﬁrst approachinthe

treatment of dyslipidemia, related or not to HIV, and our

resultscorroboratethisﬁndings.27 _In_conclusion,_any

inter-ventiontotackledyslipidemiainchildrenmustaimatnotonly

improvingnutritionqualityofthechildren,butalso,whenever

possibleavoidingtheuseofARVthatwouldraisecholesterol

ortriglyceridelevels,suchaslopinavir/ritonavir.28

Thedesignofthisstudy was cross-sectionaland aimed

onlytodescribethepresenceofLSHIVandfactorsassociated

withdyslipidemia amongchildrenfollowed at the IPPMG’s

outpatientclinic. Someofthevariables,suchastheuse of

stavudineandlackofphysicalactivity,althoughbiologically

plausiblewerenotassociatedwithdyslipidemiainourstudy,

possiblyduetothesmallsamplesizeavailable.

Webelievethatlongitudinalstudiestoinvestigatetherole

ofdietonLSHIVpreventioninthispopulationmustbe

pur-sued.

Funding

ThestudywassupportedbyFundac¸ãodeAmparoaPesquisa

doEstadodoRiodeJaneiro–JovemCientistadoNossoEstado

–CristinaBarrosoHofer–2008.

Thiswork was carried out by the Instituto de

Puericul-turaePediatriaMartagãoGesteirawithtechnicalandﬁnancial

supportoftheMinistryofHealth/SecretariatofHealth

Surveil-lance/National STD and Aids Programme (MOH/SHS/NAP)

throughtheProjectofCooperationAD/BRA/03/H34between

theBrazilianGovernmentand theUnitedNationsOfﬁceon

DrugsandCrime–UNODC.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

Ethical

approval

ThisstudywasapprovedbyIPPMG–EthicalCommittee.

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