Non-AIDS-related comorbidities in people living with HIV-1 aged 50 years and older: The AGING POSITIVE study

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Non-AIDS-related

comorbidities

in

people

living

with

HIV-1

aged

50 years

and

older:

The

AGING

POSITIVE

study

Rosário

Serrão

a

,

Carmela

Piñero

a

,

Jorge

Velez

b

,

Daniel

Coutinho

b

,

Fernando

Maltez

c

,

Sara

Lino

c

,

Rui

Sarmento

e

Castro

d

,

Ana

Paula

Tavares

d

,

Patrícia

Pacheco

e

,

Maria

João

Lopes

e

,

Kamal

Mansinho

f

,

Ana

Cláudia

Miranda

f

,

Isabel

Neves

g

,

Ricardo

Correia

de

Abreu

g

,

Joana

Almeida

h,

*

,

Leonor

Pássaro

h

a

DepartmentofInfectiousDiseases,CentroHospitalardeSãoJoão,Porto,Portugal

b

DepartmentofInfectiousDiseases,CentroHospitalardoBaixoVouga,Aveiro,Portugal

c

DepartmentofInfectiousDiseases,CentroHospitalarLisboaCentral,HospitalCurryCabral,Lisboa,Portugal

d

DepartmentofInfectiousDiseases,CentroHospitalardoPorto,Porto,Portugal

e

DepartmentofInfectiousDiseases,HospitalProf.DoutorFernandoFonsecaEPE,Amadora,Portugal

f_Department_of_Infectious_Diseases,_Centro_Hospitalar_Lisboa_Ocidental,_Hospital_Egas_Moniz,_Lisboa,_Portugal g_Department_of_Infectious_Diseases,_Unidade_Local_de_Saúde_de_Matosinhos,_Matosinhos,_Portugal h

MSDLda,QuintadaFonte,PaçodeArcos,Portugal

ARTICLE INFO

Articlehistory:

Received27August2018

Receivedinrevisedform16October2018 Accepted19October2018

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Aging HIV-1infection Non-AIDScomorbidities ABSTRACT

Objective:Tocharacterizetheproﬁle ofnon-AIDS-relatedcomorbidities(NARC)intheolder HIV-1-infectedpopulationandtoexplorethefactorsassociatedwithmultipleNARC.

Methods:Thiswasamulticentre,cross-sectionalstudyincludingHIV-1-infectedpatientsaged50years, whowerevirologicallysuppressedandhadbeenonastableantiretroviraltherapy(ART)regimenforat least6months.Amultipleregressionmodelexploredtheassociationbetweendemographicandclinical variablesandthenumberofNARC.

Results:Overall,401patientswereenrolled.Themeanageofthepatientswas59.3yearsand72.6%were male.ThemeandurationofHIV-1infectionwas12.0yearsandthemedianexposuretoARTwas10.0 years. The mean number of NARC was 2.1, and 34.7% of patients had three or more NARC. HypercholesterolemiawasthemostfrequentNARC(60.8%),followedbyarterialhypertension(39.7%) andchronicdepression/anxiety(23.9%).Arterialhypertensionand diabetesmellituswerethemost frequentlytreatedNARC(95.6%and92.6%ofcases,respectively).Thelinearregressionanalysisshoweda positiverelationshipbetweenageandNARC(B=0.032,95%conﬁdenceinterval0.015–0.049;p=0.0003) andbetweenthedurationofHIV-1infectionandNARC(B=0.039,95%conﬁdenceinterval0.017–0.059; p=0.0005).

Conclusions:AhighprevalenceofNARCwasfound,themostcommonbeingmetabolic,cardiovascular, andpsychologicalconditions.NARCratesweresimilartothosereportedforthegeneralpopulation, suggestingalargersocietalproblembeyondHIVinfection.Amultidisciplinaryapproachisessentialto reducetheburdenofcomplexmulti-morbidconditionsintheHIV-1-infectedpopulation.

creativecommons.org/licenses/by-nc-nd/4.0/).

*Correspondingauthorat:MSDLda,QuintadaFonte,EdifícioVascodaGama19,2770-192PaçodeArcos,Portugal.

E-mailaddresses:rosarioserrao@chsj.min-saude.pt(R.Serrão),maria.calvo@chsj.min-saude.pt(C.Piñero),11346@chbv.min-saude.pt(J.Velez),

Daniel.Coutinho.18237@chbv.min-saude.pt(D.Coutinho),fmaltez@chlc.min-saude.pt(F.Maltez),sara.lino@chlc.min-saude.pt(S.Lino),rsarmento@chporto.min-saude.pt

(R.SarmentoeCastro),anaprat@chporto.min-saude.pt(A.P.Tavares),patricia.p.pacheco@hff.min-saude.pt(P.Pacheco),maria.lopes@hff.min-saude.pt(M.J.Lopes),

kmansinho@chlo.min-saude.pt(K.Mansinho),amiranda@chlo.min-saude.pt(A.C.Miranda),isabel.neves@ulsm.min-saude.pt(I.Neves),correia.abreu@ulsm.min-saude.pt

(R.CorreiadeAbreu),joana.almeida@merck.com(J.Almeida),leonor.passaro@merck.com(L.Pássaro).

https://doi.org/10.1016/j.ijid.2018.10.011

1201-9712/©2018MerckSharp&DohmeCorpandTheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseasesThisisanopenaccess articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

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Introduction

Thesuccessandwideavailabilityofcombination antiretro-viraltherapy (ART)has ledto a paradigmshift indeveloped countries from HIV being a fatal disease to a manageable chronicillness(Deeksetal.,2013).Asaresult,morbidityand mortality have decreased dramatically (Palella et al., 1998; Weberetal.,2013).Infectedindividualsarelivinglongerand theHIVpopulationisaging,withalife-expectancy approach-ingthatofthegeneralpopulation(Samjietal.,2013;Mayetal., 2014).

Anestimated10%ofpeoplelivingwithHIVworldwideareover the age of 50 years. This estimate can be as high as 50% in developedregionsandwillcontinuetoriseasARTbecomesmore readilyavailableand/orisintroducedsooner(Highetal.,2012; JointUnitedNationsProgrammeonHIV/AIDS(UNAIDS),2013).

This phenomenon has been accompanied by an increasing

number of patients diagnosed at older ages who are also

diagnosed later during the course of the disease (US Centers forDiseaseControlandPrevention(CDC), 2016;Tavoschietal., 2017).AgingoftheHIVpopulationhasledtoashiftinthecauses ofdeathofinfectedindividualsandtoagrowingimpactof non-AIDS-relatedcomorbidities(NARC) (Costagliola,2014;Schouten etal.,2014).PeopleinfectedwithHIVmaysufferfromaccelerated aging(Effros etal., 2008;Deeks2009; Pathaiet al.,2014),i.e., being considered elderly at theage of 50 years (Blancoet al., 2012),althoughthisis thesubjectof debate(Rasmussenetal., 2015).Theyalsopresentanearlieronset(Guaraldi etal.,2011) and higher prevalence (Costagliola, 2014; Smitet al., 2015)of comorbidities that are typically associated with aging. These includenon-AIDS-relatedmalignancies(Kirketal.,2007; Silver-bergetal.,2015),diabetesmellitus(Guaraldietal.,2011;Hasse etal.,2011;Vanceetal.,2011;Torresetal.,2013),hyperlipidemia (Manrique etal., 2010;Wuet al.,2012),cardiovasculardisease (Triant et al., 2007; Freiberg et al., 2013; Althoff et al., 2015), arterial hypertension (Hasse et al., 2011; Oursler et al., 2011; Torreset al.,2013),kidneydisease(Guaraldietal.,2011;Vance etal.,2011),andreducedbonemineraldensity(Triantetal.,2007; Onenetal.,2010).

Comorbiditiesareassociatedwiththenaturalagingprocess, butanincreasedriskofcomorbiditiesinolderHIVpatientshas beenlinkedtothelong-termuseofART,chronicinﬂammation, andpersistentimmuneactivationduetoHIVinfection(Strategies for Management of Antiretroviral Therapy Study Group et al., 2008;Guaraldiet al.,2011; Schoutenetal., 2014).In addition, managementofthedisease inthisagingpopulationis compli-cated by polypharmacy/drug–drug interactions and toxicity (Simone and Appelbaum, 2008). For instance, interactions of some lipid-lowering agents or anticonvulsants with ART regi-menshavebeenreported(Lennoxetal.,2014;Rockstrohetal., 2013;UniversityofLiverpool,2018).Thisraisesnewtreatment challenges that require improved clinical management and optimizationofhealthresourcestobetteraddress theneedsof thispopulation.

In2015,therewere53072peoplediagnosedwithHIVinfection inPortugal,andsincethebeginningoftheHIVepidemic,14.6%of thereportedcaseshavebeenamongpeopleaged49years.This numberincreasedtoover25%ofthe1220newlydiagnosedcases in 2014 (Direcção Geral Saúde, 2015). Despite these escalating numbers,NARCinagingHIVpatientshasnotbeencharacterizedin Portugal.

Themainpurposeofthisstudywastocharacterizetheproﬁleof NARC,concurrentmedications,anduseofhealthresourcesamong HIV-1patientsaged50years followedatHIV carecentres.In addition,factorsassociatedwiththepresenceofmultipleNARC wereanalyzed.

Methods

Studydesignandparticipants

This was a cross-sectional, observational study conducted

between November 2015 and June 2016 in seven Portuguese

centresspecializinginthemanagementofHIV/AIDS.Thesecentres aremainlylocatedintheLisbonandOportoregionsandcovered approximately60%ofHIVcasesfollowedintheoutpatientsetting inthecountryin2014(DirecçãoGeralSaúde,2015).

HIV-1-positivepatientsaged50yearswereincluded consec-utively in the studyaccordingtotheir scheduledappointment. PatientshadtohavebeenonastableARTregimenforatleast6 monthsprior toenrolment,withundetectableplasma HIVRNA (<50copies/ml)duringthesameperiod.Patientswhowereunable or unwilling tocomply withstudyproceduresaccordingtothe investigator’sjudgementwereexcluded(e.g.,notbeingmentally capableofprovidingreliableinformationregardingconcomitant medications).

Variablesandsourcesofinformation

Socio-demographicdata(age,sex,race,andcountryoforigin), addictive behaviours (smoking, i.e., currently smoking or past/ never smoked,alcoholism, andillicit druguse),HIV-1infection characteristics (mode of transmission, duration of infection, plasma HIV RNAand CD4count at presentation,last CD4/CD8 ratio,andCDCHIVstage),andARTdata(regimen,duration,and number ofpreviousregimens)wereobtainedfromthemedical recordsandthroughpatientinterview.Thedurationofinfection wasdeﬁnedasthetimeelapsedfromtheyearofdiagnosistothe yearofthestudyappointment.

The diagnosis of NARC of interest was obtained from the medicalrecordsandincludeddiabetesmellitus, hypercholesterol-emia, arterialhypertension, acute myocardial infarction,stroke, renalfailure,renallithiasis,chronichepatitisC,chronichepatitisB, emphysema/bronchitis,non-AIDS-relatedmalignancies, osteopo-rosis, and depression/chronic anxiety. These variables were consideredofinteresttotheauthors,basedontwocriteria:the reportedhighprevalenceintheagingpopulation,ortheclinical relevanceintheHIV-1-infectedpopulation.

Co-medications of interest included lipid-lowering agents, antihypertensives,antidepressants oranxiolytics,insulinor oral antidiabetics, antiplatelet or anticoagulants, bronchodilators, inhaledorothertypesofsteroid,andtreatmentsforosteoporosis. Thenumberanddurationofhospitalizationsandthenumberof medicalappointmentsattheHIVspecialist(andotherspecialties) andthegeneralpractitionerovertheprevious12monthswerealso collected.

Thestudywasapprovedbytheethicscommitteeofeachcentre and allparticipantsprovidedwritteninformedconsentpriorto enrolment.

Statisticalanalysis

Continuousvariablesweresummarizedasthemean,median, standard deviation (SD),and/or range and categorical variables weresummarizedastheabsoluteandrelativefrequencies.

The associationbetween thepresenceandnumberof NARC and the following independent variables of interest were explored: sex,age, duration of infection andART (cut-offs for the lasttwo variables were 6 months–1 year,1–5years, 5–10 years, 10–15 years, 15–20 years, and 20 years), time to presentation (late presentation: CD4 count <350cells/mm3_; non-late presentation: CD4 count 350cells/mm3_),_CD4 _count <200cells/mm3_,_and_last_CD4/CD8_ratio.

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The Chi-square test and Kruskal–Wallis non-parametric test wereusedtoexploretheassociationofcategoricalandcontinuous independentvariables of interest withthe grouped number of NARC(0,1,2,3).TheKruskal–Wallistestwasusedtocompare ARTregimens regarding NARC and co-medications. Spearman’s correlationcoefﬁcientwasusedtocorrelatethenumberofNARC withthedurationofinfection,durationofART,lastCD4/CD8ratio, anduseofhealthresources.

Theassociationbetweencategoricalandcontinuous indepen-dentvariablesofinterestandthepresenceofatleastoneNARCwas measuredwith theChi-square test (orFisher’s exact test) and Mann_–Whitney non-parametric test for continuous variables, respectively.

A multivariable linear regression model (beta regression coefﬁcient,B)and95%conﬁdenceintervals(95%CI)andp-values wereusedtodeterminetheassociationofindependentvariables withthenumberofNARC.

Allvariablesofinterestwithp<0.20inthebivariateanalysis wereincluded in the multivariableregression model. Onlythe variables with statistically signiﬁcant B were included in the optimizedlinearmodel.Goodness-of-ﬁt wasassessedusingthe R-squaredtest(R2₎_for_the_number_of_NARC.

All comparisons were two-tailed and statistical signiﬁcance wassetat5%.SASsoftwareversion9.4(SASInstituteInc,Cary,NC, USA)wasusedforallanalyses.

Results

Socio-demographicandclinicalcharacteristics

Overall,401patientswereincluded,ofwhom72.6%weremale. Themeanageofthestudypatientswas59.37.5years(Table1). Nearlyhalfofthepatients(47.6%)werepastorcurrentsmokers, 7.7%werechronicalcoholics,and17.2%werepastorcurrentusers ofillicitdrugs.

Themean durationof HIV-1infectionwas 12.06.2years andthemostfrequentmodeoftransmissionwasheterosexual contact (66.3%). The median CD4 count at presentation was 272cells/mm3_,_with_59.3%_of_patients_being_late_presenters_(CD4 count<350cells/mm3₎_and _41% _of _patients _presenting _a _CD4 count<200cells/mm3.ThemedianvalueofthemostrecentCD4 countwas589cells/mm3_._A_mean_increase_of₃₂₇_CD4_cells/mm3 wasobservedbetweenthelatestCD4countandthe measure-mentobtainedatpresentation.AnAIDSdiagnosiswasmadein 44.6%ofpatients(Table1).

HIV-1treatmentanduseofhealthresources

ThemeandurationofexposuretoARTwas10.4years,with8.0% ofpatientshaving receivedthetreatmentfor20 years ormore (Table2).ThemediantimefromdiagnosistoinitiationofARTwas 1.62.7years.ThemeancumulativenumberofARTregimenswas 3.01.93, and 19.5% of patients had received ﬁve or more regimens.ThemediandurationofthecurrentARTregimenwas 2.0years(range0.0–15.0years)andthemostfrequentclassofART usedwasnon-nucleosidereversetranscriptaseinhibitors(NNRTI) (52.9%ofpatients), followedby proteaseinhibitors(24.4%) and integraseinhibitors(17.0%).

Allpatientshadattendedatleastoneappointmentwithan HIV specialist in the previous 12 months (median of three appointments,range1–43appointments),49.0%hadattended

other specialist appointments, and 56.4% had attended

appointments at the general practitioner. Twenty-eight

patients (7.2%) had been hospitalized in the previous year (meanof1hospitalization),withamediandurationof7days (range1–37days).

NARCandco-medications

Thelargemajorityofpatients(90%)hadatleastoneNARC(the meannumberwas2.1andmedianwas2.0(range0–6))andnearly 35%hadthreeormoreNARC(Table3).ThemostfrequentNARC washypercholesterolemia(60.8%ofpatients),followedbyarterial hypertension (39.7%). Other NARC included chronic anxiety/ depression(23.9%ofpatients),chronichepatitisC(14.2%),diabetes mellitus(13.5%),andrenallithiasis(11.2%).

Nearly half of the patients(49.6%) werebeing treated with lipid-loweringagents,followedbyantihypertensives(39.4%)and antidepressant/anxiolyticdrugs(17.7%)(Table3).

Table1

Socio-demographicandHIV-1infectioncharacteristicsofthestudyparticipants. Totalnumberofparticipants 401

Age(years),meanSD(range) 59.47.5(50–87) Sex Male 291(72.6) Female 110(27.4) Race Caucasian 365(91.2) Other 35(8.8) Missing 1 Countryoforigin Portugal 372(92.8) Other 29(7.2) Smokinghabits

Smoker(pastorcurrent) 191(47.6)

Non-smoker 210(52.4)

Chronicalcoholism

Yes 31(7.7)

No 370(92.3)

Illicitdruguse

Never 332(82.8)

Past 59(14.7)

Current 10(2.5)

Durationofinfectiona_(years),_mean_SD_(range) _12.0_6.2_(1–29) Modeoftransmission

Heterosexualcontact 266(66.3) Menwhohavesexwithothermen 65(16.2) Intravenousdruguse 59(14.7)

Parenteral 1(0.2)

Other 10(2.5)

PlasmaHIV-1RNAatpresentation(copies/ml), median(range)

102000(20–1107₎

Missing 68

CD4countatpresentation(cells/mm3

),median(range) 272(1–1255)

Missing 40

Latepresentation(CD4<350cells/mm3

) Yes 214(59.3) No 147(40.7) CD4<200cells/mm3 Yes 148(41.0) No 213(59.0)

LastCD4count(cells/mm3

),median(range) 589(10–2195) ChangeinCD4countb

(cells/mm3

),meanSD 327319

Missing 40

CD4/CD8ratio–lastmeasurement,median(range) 0.80(0.10–3.40) CDCHIV-1stagec A1 78(20.1) A2 106(27.3) A3 50(12.9) B1 10(2.6) B2 21(5.4) B3 19(4.9) C1 7(1.8) C2 11(2.8) C3 86(22.2)

SD,standarddeviation.Dataarepresentedasthenumberandpercentage,unless otherwisespeciﬁed.Reasonsfornon-eligibilityincludedchangeofARTregimenin thepast6months(n=1)andpatientinabilitytoprovidereliableinformationduring thestudyappointment(n=1).

a

Timeelapsedfromtheyearofpresentationtotheyearofstudyappointment.

b

FrompresentationtolastCD4cellcount.

c

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Ofthepatientswitharterialhypertension,95.6%werebeing treatedwithantihypertensivesatthetimeofthestudy appoint-mentand92.6%ofthepatientswithdiabetesmellituswerebeing treated with insulin or oral antidiabetics. Chronic hepatitis B, hypercholesterolemia,osteoporosis, acutemyocardialinfarction, anddepression/chronicanxietyweretheotherconditionswhere theproportionofpatientsontreatmentwasabove70%.

Associationofindependentvariablesofinterestwiththenumberof NARC

ThebivariateanalysisshowedthatageanddurationofHIV-1 infectionweresigniﬁcantlyassociatedwiththenumberofNARC (SupplementarymaterialTableS1).

The optimized multiple linear regression model showed

modest statistically signiﬁcant effects regarding age (B=0.032, 95%CI0.015–0.049;p=0.0003) anddurationof HIV-1infection (B=0.039,95% CI 0.017–0.059; p=0.0005) withthe number of NARC(Table4).

Table 5 shows the associations between the use of health

resources and the number of NARC. The number of medical

appointments at non-HIV hospital specialists (r=0.2112; p=0.0032) and the number of co-medications (r=0.7511; p<0.0001)werecorrelatedwiththenumberofNARC.

Forthethreemostprevalent ARTregimens(NNRTI,protease inhibitors,andintegraseinhibitors),themediannumberofNARC

was2.0(p=0.003).Nostatisticallysigni_ﬁcantdifferencewasfound between theseART regimens regarding themedian number of co-medications(p=0.077;datanotshown).

Discussion

Inthisstudy,itwasfoundthatthevastmajority(90%)of HIV-1-infectedpatientsaged50yearsandolderhadatleastoneNARC. Thisprevalenceisparticularlyhighwhencomparedtocohortand cross-sectional studiesfromotherregions,whichhavereported oneormoreNARCin50–70%ofolderHIVpatients(Hasseetal., 2011;Rodriguez-Penneyetal.,2013;Torresetal.,2013;Wuetal., 2014). However, two surveys conducted in the USA showed a prevalence of NARCover 90% (Brennan,2009; Baldersonet al., 2013).In addition,patientsin thepresentstudyhadanaverage numberoftwoNARC,whichislowerthanotherstudiesthathave reportedanaverageoffourormore(Vanceetal.,2011;Balderson etal.,2013).OnethirdofoursamplehadthreeormoreNARC.

ThemostcommonNARCwashypercholesterolemia. Interest-ingly, the prevalence found is disproportionately higher when compared toreports fromothercountries(60%vs.30%)(Torres etal.,2013;Wuetal.,2014).Itisknownthathypercholesterolemia iscommonlyassociatedwithlong-termuseofART(Riddleretal., 2007)andthatbothproteaseinhibitorsandNucleosideReverse TranscriptaseInhibitor(NRTI)areassociatedwithHIVmetabolic

Table2

Antiretroviraltherapiesanduseofhealthresources. Numberofparticipantsa

400 ARTdurationb

(years),median(range) 10.0(1–27) 6months–1year 0(0.0) 1–5years 87(21.8) 5–10years 111(27.8) 10–15years 93(23.3) 15–20years 77(19.3) 20years 32(8.0)

NumberofARTregimens,meanSD 3.01.9 Patienthad5ARTregimens

No 322(80.5)

Yes 78(19.5)

TimefromdiagnosistoARTinitiation(years), median(range)

1.62.7 CurrentARTdurationc

(years),median(range) 2.0(0.0–15.0) ARTatstudyappointment

Proteaseinhibitors(PI) 98(24.4)

NNRTI 212(52.9)

Integraseinhibitors 68(17.0)

PI+NNRTI 1(0.2)

OtherART 22(5.5)

Useofhealthresourcesoverthepast12months

MedicalappointmentsatHIVspecialist(n=394) 394(100.0) NumberofappointmentsatHIVspecialist,

meanSD(range)

3.432.72(1.0–43.0) Appointmentsatotherspecialty(n=384) 188(49.0)

Numberofappointmentsatotherspecialty, meanSD(range)

3.503.48(1.0–25.0) Appointmentsatgeneralpractitioner(n=275) 155(56.4)

Numberofappointmentsatgeneralpractitioner, meanSD(range)

3.583.48(1.0–17.0) Hospitalizationsduringthepreviousyear(n=391) 28(7.2)

Numberofhospitalizations,meanSD(range) 1.110.31(1–2) Durationofhospitalization(days),median(range)

(n=31)

7.0(1–37)

ART,antiretroviraltherapy;SD,standarddeviation;NNRTI,non-nucleosidereverse transcriptaseinhibitor.Data are presentedasnumberand percentage,unless otherwisespeciﬁed.

a

Samplefromwhichproportionswerecalculated.

b

YearselapsedfromﬁrstARTtostudyappointment.

c

Forincompletedates,thefollowingassumptionswereconsidered:ifonlythe yearwasknown,thedateconsideredwasJuly1;ifonlythedaywasunknown,the 15thdayofthegivenmonthwasconsidered.

Table3

Non-AIDS-relatedcomorbiditiesandco-medications.

Totalnumberofparticipants 401 Atleastonenon-AIDS-relatedcomorbidity,n(%) 361(90.0)

1 116(28.9) 2 106(26.4) 3 139(34.7) Non-AIDS-relatedcomorbidities MeanSD 2.11.34 Median(range) 2.0(0–6)

Distributionofnon-AIDS-relatedcomorbidities,n(%)

Hypercholesterolemia 244(60.8) Arterialhypertension 159(39.7) Depression/chronicanxiety 96(23.9) ChronichepatitisC 57(14.2) Diabetesmellitus 54(13.5) Renallithiasis 45(11.2) Emphysema/bronchitis 36(9.0) Non-AIDS-relatedmalignancy 32(8.0) Renalfailure 32(8.0) Osteoporosis 23(5.7) ChronichepatitisB 17(4.2) Acutemyocardialinfarction 14(3.5)

Stroke 15(3.7)

Co-medicationsofinterestatstudyappointment,n(%)

Lipid-loweringagents 199(49.6) Antihypertensives 158(39.4) Antidepressants/anxiolytics 71(17.7) Insulin/oralantidiabetics 52(13.0) Antiplatelet/anticoagulants 46(11.5) Bronchodilators,inhaledsteroidsorothers 27(6.7) Osteoporosistreatment 24(6.0) HepatitisCtreatment 7(1.7) NARCbeingtreatedatstudyappointment,n(%)

Arterialhypertension 152(95.6) Diabetesmellitus 50(92.6) Acutemyocardialinfarction 12(85.7) Hypercholesterolemia 194(79.5) Osteoporosis 18(78.3) Stroke 11(73.3) Depression/chronicanxiety 68(70.8) Emphysema/bronchitis 24(66.7) ChronichepatitisCa 7(12.3) SD,standarddeviation;NARC,non-AIDS-relatedcomorbidities.

a_Of _the _patients _not _being _treated _for _chronic _hepatitis _C _at _the _study

appointment,72.0%(41/50)werecuredfromthisinfectionand11.0%(9/50)were awaitingtreatment.

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syndrome(Jericoetal.,2005),whichishighlyprevalentin HIV-infected patients (Gazzaruso et al., 2002). However, protease inhibitorswereusedonlybyonequarterofparticipants.Moreover, the duration of ART was not signiﬁcantly associated with hyperlipidemiaintheregressionanalysis.Therefore,itisplausible toassumethatfactorssuchasdietandlifestylecouldlargelyhave contributed to the high prevalence of dyslipidemia among participants. Epidemiological studies conducted in Portugal showeda prevalenceofhypercholesterolemiavaryingfrom56% to69%(InstitutodeAlimentaçãoBECEL,2000;Costaetal.,2003). The Socrates study revealed that hypercholesterolemia was frequently associated with higher body mass index, arterial hypertension,and familial history of highcholesterol (Perdigão etal.,2010).

Arterial hypertension and depression/anxiety were other

common NARC in this study (approximately 40% and 24%,

respectively), with proportions that corroborate other reports (Manrique etal., 2010;Guaraldietal., 2011;Hasse etal., 2011; Vanceetal.,2011;Wuetal.,2012,2014;Torresetal.,2013).When comparingtheprevalenceofNARCobtainedinthisstudywiththe NARCdistributionavailablefromthePortugueseHealthNational Inquiryof2014forthegeneralpopulation45yearsofage,we foundasimilarprevalenceofarterialhypertension(39%vs.41%, respectively)andslightlyhigherprevalenceofdepression/anxiety (23.9%vs.16.7%)(ServiçoNacionaldeSaúde,2014).Inaddition,a comparableprevalencewas foundfor diabetes(13.5%vs.15.8%, respectively),emphysema/bronchitis(9.0%vs.8.2%),stroke(3.7% vs. 2.6%), and acute myocardial infarction (3.5% vs. 2.4%). The similardistribution of NARC rates found betweenHIV-infected individualsandthegeneralpopulationsuggestsalargersocietal problemthatisnotrestrictedtotheHIVinfectionsetting.Factors relatedtotheagingprocessandtochronicdiseasesmaybestrong contributorstotheNARCdistributionobserved.

ItwasfoundthatthedurationofHIV-1infectionhadamodest statisticallysigniﬁcanteffectconcerningthenumberofNARC,even whenadjustedforage.

Some studies have shown that longer ART exposure is an independent predictor of polypathology (Phillips et al., 2008; Guaraldietal.,2011).However,inthelinearregressionmodel,a

statisticalassociationbetweenthisindependentvariableandthe numberofNARCwasfound.

Notsurprisingly,thedistributionofco-medicationsbeingused at the time of the study appointment was in line with the distribution of NARC,with lipid-loweringagents, antihyperten-sives, and antidepressants/anxiolytics being the most frequent. Arterial hypertension and diabetes mellitus were the most medicated conditions, with over 90% of patients receiving treatment.

Of note, thehigh proportion of chronic hepatitis C patients withouttreatmentatthestudyappointmentwasduetothefactthat they were already cured of theinfection or were still awaiting treatment.Despitethesmallnumbersanalyzed,this_ﬁndingshould beplacedinthecontextoftheemergingcureratesresultingfromthe useofdirect-actingantiviralsinPortugalsince2015.Itisexpected thattheepidemiologypatternandmanagementofHIV/hepatitisC virusco-infectionwillchangesubstantiallyinthenearfuture.

Surprisingly,nocorrelationwasfoundbetweenthenumberof co-medicationsandthenumberofNARC.Onepossibleexplanation for this finding is that despite the diagnosis of a comorbid condition, patients do not necessarily take the prescribed medication (e.g.,low financial resources or tryingprophylactic approachesfirst,suchasdietorexerciseamongthepatientswith lipiddisorders).Thereverseisalsotrue,withpatientsoften self-prescribingmedicationswithouthavingtheconditionconcerned (e.g.,antidepressants).

PatientswithahighernumberofNARCweremorelikelytovisit thenon-HIVspecialist.

TheMSMmodeoftransmissionwas16%,whichislowerthan thatdescribedinotherEuropeanreports.In2012,MSMaccounted for 41.7%of newly reported HIV diagnoses in Western Europe (European Centre for Disease Prevention and Control/WHO Regional Ofﬁce for Europe, 2013; Nakagawa et al., 2014). An epidemiological study conducted in the northern region of Portugal showed that only 26 out of the 289 individuals (9%) reported MSM transmission (Carvalho et al., 2015). The highly conservativecultureofthePortuguesepopulationmayexplainthe lowerriskofMSMtransmissionintheolderindividualscompared tootherEuropeanpopulationsofthesameagegroup.

Table4

Multivariablelinearregressionmodelregardingthenumberofnon-AIDS-relatedcomorbidities.a

Initialmodel Optimizedmodel

B 95%CIforB p-Value B 95%CIforB p-Value Sex,n(%)

Male Reference

Female 0.233 0.055to0.52 0.112

Age(years) 0.032 0.015to0.049 0.0002 0.032 0.015to0.049 0.0003 Durationofinfection(years)b

0.038 0.017to0.059 0.0004 0.039 0.017to0.059 0.0005

p-Value <0.0001 <0.0001

R2 _0.052 _0.049

B,betaregressioncoefﬁcient;CI,conﬁdenceinterval;R2

,R-squaredwasusedtotestthegoodness-of-ﬁtofthemodel.

a

The‘durationofinfection’andthe‘durationofART’wereeligibleforinclusioninthemultivariablemodel.However,duetothehighcorrelationbetweenthetwovariables, onlytheformerwasincludedasitshowedahigherassociationwiththetotalnumberofnon-AIDS-relatedcomorbidities.

b

Durationofinfectionwasincludedasacontinuousvariable.

Table5

Associationbetweentheuseofhealthresourcesandthenumberofnon-AIDS-relatedcomorbidities.

Spearman’scorrelationcoefﬁcient p-Value NumberofNARCvs.numberofmedicalappointmentsattheHIVspecialist 0.0804 0.1113 NumberofNARCvs.numberofmedicalappointmentsatotherhospitalspecialist 0.2136 0.0032 NumberofNARCvs.numberofmedicalappointmentsatgeneralpractitioner 0.0867 0.2934 NumberofNARCvs.numberofhospitalizationsduringthepreviousyear 0.0147 0.9408 NumberofNARCvs.numberofco-medications 0.7511 <0.0001 NARC,non-AIDSrelatedcomorbidities.

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DespitePortugalhavingalargepopulationofmigrants,thevast majorityofindividualsinthesamplewereCaucasian(>90%).This couldbeexplainedbythefactthatmigrantsinPortugalareusually lesscompliantwithHIVclinicalappointments.

This study is subject to some limitations. First, specific diagnosiscriteriafor NARCwerenotpreviewed in theprotocol andthesedataweredrawnfromthemedicalrecords.Apotential heterogeneityofdiagnosispracticesacrossinstitutionscannotbe excluded.Regardinghypercholesterolemia,thecriteriadefinedin theEuropean Society ofCardiology(ESC) guidelinesare widely adoptedbyphysiciansinPortugal(Brignoleetal.,2018).Second,an age-matched HIV-1-uninfected populationwas not included to comparethefrequencyofNARC,co-treatments,oruseofhealth resources.Nevertheless,itwasfoundthatthedistributionofthe mostprevalentNARCinthisstudywascomparabletotheNARC distributionforthegeneralpopulationin2014forasimilarage stratum.Furthermore,thisstudyfocusedonlyoncomorbiditiesof interest,thosethataremorefrequentlyassociatedwiththeaging processorfoundintheHIV-infectedpopulation.Capturingother comorbidconditionswouldcertainlyenrichthefindings.PastART regimenswerenotcaptured,soitwasnotpossibletoexploretheir associationwithcurrentconditionssuchasmetabolicsyndrome. Inaddition,duetothecross-sectionaldesignofthestudy,those patientswithabetterprognosisandmoreengagedindealingwith theirHIVinfectionmayhavebeenincluded.Thissurvivalbiasmay havemoreofanimpactintheolderagestratum.

Themajorityofparticipatingsitesdidnotsystematicallycollect thereason for non-eligibility. Althougha consecutive sampling methodwasimplemented,whichpotentiallyminimizesselection bias,thetruemagnitudeofbiasinthisstudycannotbeascertained. Inconclusion,thisstudyprovidesapictureoftheolder HIV-1-infectedpatientinPortugal,revealingaveryhighprevalenceof NARC.Thisposesseveralchallengesregardingthemanagementof thisconditionandtheneedtoadoptadequatetreatmentstrategies todealwiththispotentiallypolymedicatedpopulation, particu-larlyinregardtotheinteractionsofNNRTIsandproteaseinhibitors withco-medications.

A multidisciplinary approach involving the expertise of differentﬁeldsof health careis essential toreducetheburden ofcomplexmulti-morbidHIVinfectioninolderpeople.

Acknowledgements

Medical writing and/oreditorial assistance was providedby LuísVeloso,BSc,ofEurotrials—ScientiﬁcConsultants,Lisboa.This assistancewasfunded byMerckSharp&Dohme,Lda,Portugal. StatisticalsupportwasprovidedbyVeraVicente,BSc,ofEurotrials — ScientiﬁcConsultants, Lisboa and funded by Merck Sharp & Dohme,Lda,Portugal.

Financialsupport

MerckSharp&Dohme,Lda,Portugalprovidedﬁnancialsupport forthenon-interventionalstudy(ProtocolNr.MK0518-826). Conﬂictofinterest

JA and LP are employees of MSD Portugal. FM provides

consulting services, communications, teaching and research support,aswellaspublicationsforAbbVie,Bristol-MyersSquibb, GileadSciences,Janssen-Cilag, MerckSharp&Dohme, andViiV Healthcare.ACMhasreceivedunrestrictedresearchgrantsoracted asaspeakerorasconsultantforMerckSharp&Dohme, Gilead Sciences, AbbVie, ViiV HealthCare, Janssen-Cilag and Roche pharmaceutics.JVhascollaboratedonadvisoryboardsforAbbVie, GileadSciences,Janssen-Cilag, MerckSharp&Dohme,andViiV,

and has receivedspeaker honorariafromBristol-Myers Squibb, GileadSciences,Janssen-Cilag,MerckSharp&Dohme,andRoche. CPhasactedasaspeakerinlectures,courses,andadvisoryboards for MerckSharp&Dohme, ViiV,andJanssen-Cilagand hasalso receivedfinancialsupportfromMerckSharp&Dohme, Janssen-Cilag, Gilead Sciences, AbbVie, and ViiV, to participate in congressesandcourses.Atthemoment,sheisaco-investigator in clinicaltrialssponsoredbyMerck Sharp&Dohme,ViiV, and GileadSciences.INhasreceivedhonorariaforadvisoryboardsand hasreceived financialsupport fromJanssen-Cilag,ViiV, Health-Care,MerckSharp&Dohme,andGileadSciencestoparticipatein courses. RCA has received honoraria for advisory boards from GileadSciences,Janssen-Cilag,ViiV,GlaxoSmithKline,andMerck Sharp&Dohmeandhasreceivedfinancialsupportforresearchand consultingfromMerckSharp&Dohme.Theotherauthorsdeclare noconflictsofinterest.

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