ww w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Brief
communication
Cardiovascular
disease
in
human
immunodeficiency
virus-infection
as
a
cause
of
hospitalization:
a
case-series
in
a
General
Hospital
in
Peru
Germán
Valenzuela-Rodríguez
a,∗,
Edward
Mezones-Holguín
b,c,∗,
Fernando
Mendo-Urbina
d,
Alfonso
J.
Rodríguez-Morales
eaClínicaMédicaCayetanoHeredia,Lima,Peru
bUnidaddeGeneraciónyAnálisisdeEvidenciasenSaludPública(UNAGESP),InstitutoNacionaldeSalud,Lima,Peru cSchoolofMedicine,UniversidadPeruanadeCienciasAplicadas,Lima,Peru
dInfectiousDiseasesService,HospitalNacionalEdgardoRebagliatiMartins,EsSalud,Lima,Peru
eResearchGroupPublicHealthandInfection,FacultyofHealthSciences,UniversidadTecnológicadePereira(UTP),Pereira,Risaralda,
Colombia
a
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t
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c
l
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Articlehistory:
Received1December2014 Accepted5March2015 Availableonline16April2015
Keywords: Cardiovasculardiseases HIV AcquiredImmunodeficiency Syndrome Peru
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Background:Cardiovasculardiseaseinthecontextofhumanimmunodeficiencyvirus infec-tionhasbecomeamajorclinicalconcerninrecentyears.Inthecurrentreportweassess hospitalizationsduetocardiovasculardiseaseinhumanimmunodeficiencyviruspatients inaSocialSecurityreferencehospitalinPeru.
Methods:AretrospectivestudywascarriedoutbetweenJanuary1996andDecember2012in aGeneralHospitalinLima,Peru.
Results:Weincluded26patientshospitalizedduetocardiovasculardisease.Meanagewas 46.3years(SD12.5),predominantlymale(57.7%).Tenpatients(38.4%)wereinAcquired ImmunodeficiencySyndromestages.Seventeen(65.4%)receivedhigh-active-antiretroviral therapy.Eleven(42.3%)hadcardiacinvolvementand15(57.7%)hadnon-cardiacvascular involvement.Themostfrequentcausesofcardiacinvolvementwerepericardialeffusion andmyocardialinfarction.Ontheotherhand,deepveinthrombosisandstrokewerethe mostfrequentfornon-cardiacvascularinvolvement.
Conclusions: CardiovasculardiseaseisanimportantcauseofhospitalizationinPeruvian humanimmunodeficiencyviruspatients,withdifferencesbetweenimmunosuppression stages.Furtherstudiesanalyzingassociatedfactorsarewarranted.
©2015ElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthors.
E-mailaddresses:germanvrodriguez@yahoo.com(G.Valenzuela-Rodríguez),emezones@gmail.com(E.Mezones-Holguín). http://dx.doi.org/10.1016/j.bjid.2015.03.001
Humanimmunodeficiencyvirus(HIV)infectionhasbeen characterizedbysignificant immunosuppressionstatesthat predispose patients to opportunistic infectious and neo-plasias, as well as progressive dysfunction of organs and systems.1 Since 1981, HIV infection, and particularly the
Acquired Immunodeficiency Syndrome (AIDS), has evolved drasticallyfromanacutelethalcondition,withnotherapeutic options,toachronicdiseasewithmultipleavailable therapeu-ticregimens.2Unfortunately,AIDSepidemicaffectsprimarily
youngadults,includingapercentageofskillededucated per-sonscausinghigh economicimpact.Furthermore,it isstill associatedwithstigmathatcouldprobablylimittheresponse tothisepidemic.3InLatin-Americathereareimportant
dif-ferencesbetweencountries.AccordingtodatafromONUSIDA andCELADE,in2010therewere75,000HIV-infectedpatients inPeruwithaprevalenceof2.5per1000inhabitants,being sexualintercoursethemostimportantrouteoftransmission (97%).4
Highlyactiveantiretroviraltherapy(HAART)significantly reduced morbidity and mortality related to AIDS-defining opportunistic diseases (ODs).4 Since the introduction of
dideoxynucleosidereversetranscriptaseinhibitors(NRTIs)in 1985 and after the approval of the first protease inhibitor in 1995, the availability of new fixed-dose combinations regimens ofnewantiretroviral drugs, evolved fasterinthe developedworld.Unfortunately,this isnotthesituation in low- and middle-income countries, especially in the rural setting,whereHIVnowiscommon.5 Thesuccessfulroleof
HAARThasextendedlifeexpectancyandenhancedthe over-all well-being ofHIV-infected individuals.Moreover,recent reportsdemonstratedthatHAARTcouldbeusefulstrategyin prevention,aswellasintreatment,pointouttheimportance ofdrugadherence.4,5InPeru,EsSalud,amajorsocialsecurity
healthprovider, incorporated HAARTin 2001with increas-ingcoverage,asthemedicalandpatientcommunitiesreadily acceptedit.4
However,thereareincreasedconcernsregarding HAART-mediatedmetabolicderangementsanditspotentialriskfor cardiovascular diseases (CVD) in the long term,1,3,5
espe-cially when certain classes of antiretroviral drugs, such as the protease inhibitors (PIs) are strongly implicated in this process.6 CVD in HIV infection may result from
cardiacinvolvementuponpresentationofODsinthe pres-enceofadvancedimmunosuppression,beaconsequenceof HIV-induced immuneactivation or derive from antiretrovi-raltherapy-associateddyslipidemiaandinsulinresistance.7
Besidesthat,suchconsequenceshavenotbeenparticularly addressedinLatinAmericancountries,includingPeru.1–7
CVDin patients with HIVinfection, must be diagnosed andtreated,becausethereisgrowingincidence,dueto fac-torsassociatedwiththe infection orwiththe use ofsome therapies.6AccordingtotheJointUnitedNationsProgramon
HIVand AIDS(UNAIDS) 2013report,it hasbeen estimated that 35.3 million were infected all over the world in 2012 (32.2million–38.8million).However,theannualincidenceof newcasesaredecreasingasaconsequenceofHAARTuse.8
Nonetheless,ifononehandnewcomplextherapeutic regi-menshavefavorablyimpactedlifeexpectancy,ontheother hand some clinical situations like CVD or adverse events havebecomeveryrelevant.6,9 Investigationsassessingthese
negativeconsequencesofHAARTshouldbeconductedin sett-ingslikePeru,wheretherehavenopreviousstudies.10–15
Therefore, the aim our study was to describe the CVD complications asacause ofhospitalizationinHIV-infected patients, ineverystageofdisease,inaGeneralHospitalof SocialSecurityinLima,Peru.
Wecarried outaretrospective observationalstudy (case series)attheEdgardoRebaglatiMartinsHospital,areference hospitalfrom PeruvianSocial Security(EsSalud),with1500 beds, atLima,Peru. Thisreport corresponds tothe period betweenJanuary1996andDecember2012.
EveryhospitalizationattheInfectiousDiseasesUnit dur-ingthestudyperiodwasreviewed,lookingforthediagnosis ofHIVinfectionthatoughttobedescribedinthediagnosis list filled in at hospital admission and discharge. At dis-charge, diagnosis of“acute pericarditis”, “other diseasesof pericardium”, “unstable angina”, “acute myocardial infarc-tion”,“myocarditis”,“acuteandsubacuteendocarditis”,“heart failure”, “cerebral infarction”, “intracerebral hemorrhage”, “thrombophlebitis”, “pulmonary embolism”, and “primary pulmonaryhypertension”,accordingtoICD-10classification, werereviewed.
Cardiovascularriskfactorsweredefinedasfollows:arterial hypertension according to recommendations of the Sev-enth JointNationalCommitteeorifthepatientreportedto be on hypertensive treatment; diabetes was defined if the patienthadglucoselevelof126mg/dLorgreaterintwo sep-arateoccasions, orifthe patientwasontreatmentforthis condition. Dyslipidemia was considered if the patient had total cholesterolof 200mg/dL or greater, or were receiving hypocholesterolemicdrugs.Obesitywasconsideredwhenin patients with a body mass index of 30 or greater. Finally, apatientclassified assmokerif hesmoked anynumberof cigarettes atthe timeofhospitaladmission orhadquitted smokinglessthanayearbefore.
Data of clinical records of the eligible patients were abstractedusingaformbuiltforthisstudy.Analysiswas per-formedusingtheStatisticalPackageforSocialScience(SPSS) version 21.0 (IBMCorporation 1994,2014,USA). At descrip-tive level numeric variables were presented asmeans and standard deviations(SD)iftheyhad normaldistributionor withmediansandinterquartileranges(IQR)iftheyhadnot. Categoricalvariablesareshowedasabsolutefrequenciesand percentages.
We included 26 hospitalized HIV-infected patients with CVD in study period. Nopatient had more than one hos-pitalization forthe same reason. Meanage was 46.3 years (SD12.5),andwerepredominantlymale(57.7%).Tenpatients (38.4%)fulfilledthedefinitionofAIDS.Outofthe17(65.4%) patients who had receivedHAART, eighthad received pro-teaseinhibitors.TheoverallmediantimeofHAARTusewas48 months(IQR72),andofHAARTincludingproteaseinhibitors was72months(IQR90).
Prevalence of cardiovascular risk factors was low, with 15.4%witharterialhypertensionanddyslipidemia,andtype 2diabetesorsmokingin7.7%(Table1).
Elevenpatients(42.3%)hadsometypeofcardiacalteration and15(57.7%)hadsometypeofvascularnon-cardiac prob-lem.Themostfrequentlycardiacalterationswerepericardial effusion (15.4%) and myocardial infarction (11.5%); among
Table1–Demographicandclinicalvariablesof HIV-infectedpatientswithcardiovasculardiseasesat EdgardoRebagliatiMartinsHospital,Lima,Peru, 1996–2012. Variable Mean(SD)/n(%) Age(years) 46.3(12.59) 30–75(range) Gender Male 15(57.7%) Female 11(42.3%)
TimeofHIVdiagnosis(months) 36(12–72)
AIDSstage Yes 10(38.4%) No 16(61.6%) CD4count(cels/ul) 170(20–323) HAART Yes 17(65.4%) Proteaseinhibitors 8(30.7%) No 9(34.6%)
Cardiovascularriskfactors
Arterialhypertension 4(15.4%)
Dyslipidemia 4(15.4%)
Type2diabetes 2(7.7%)
Smoking 2(7.7%)
Obesity 0(0%)
Table2–Frequencyofcardiovascularalterationsof HIV-infectedpatientswithcardiovasculardiseaseat EdgardoRebagliatiMartinsHospital,Lima,Peru, 1996–2012. Classification n(%) Cardiacalteration(n=11) Pericardialeffusion 4(15.4%) Myocardialinfarction 3(11.5%) Myocarditis 2(7.7%) Bacterialendocarditis 1(3.85%) Heartfailure 1(3.85%)
Vascularnon-cardiacalteration(n=15)
Deepveinthrombosis 6(23.1%)
Cerebrovasculardisease 5(19.2%)
Pulmonaryhypertension 3(11.5%)
Pulmonaryembolism 1(3.85%)
vascularnon-cardiacalterationsprevaileddeepvein throm-bosis(23.1%)andcerebrovasculardisease(19.2%)(Table2).
Cardiac involvementinHIV-infectedpatients withAIDS wasfirstdescribedin1983byAutranwhoreported myocar-dialKaposisarcomaatautopsy.Afterthat,therehavebeenan increasednumberofreportsofcardiacinvolvementinAIDS patientsrangingbetween28%and73%.Moreover,inautopsy reportsofHIV-infectedpatients,thefindingssuggestthat car-diacinvolvementisrathercommon,possiblyaffectingmore than73%ofpatients.16,17
However,withtheincreaseoflifeexpectancyofthe HIV-infected population, the incidence ofage-related diseases, such as CVD in older adults, have also increased. Such incrementinCVDhasbeenrelatedtoaging,wheresome car-diovascularriskfactorslikehighbloodpressureanddiabetes, aswellastotheuseofantiretroviraltherapies,whoseeffect
couldbedifferentdependingonthetherapeuticclassandthe individualeffectsofeverydrug.17–20
Prevalence ofthese CVDin HIV-infectedpatients varies fromcountryoforigin(developingordevelopedregions)and accordingtotheuseofHAARTandthetypeoftherapy (includ-ingprotease inhibitorsornot).Ontheotherhand,vascular involvementassociatedwithHIVinfection orits treatment couldbecardiacornon-cardiac.17–20
In Peru, there are some publications about the cardiac involvementofHIV-infectedpatients.Inastudyof164 ambu-latorypatientsfromCayetanoHeredia(MinistryofHealth)and GuillermoAlmenara(SocialSecurity,EsSalud),evaluated dur-ing2001and2002,usingechocardiography,theprevalencesof CVDcomplicationswere:pericardialeffusion9.75%,systolic dysfunction 1.82%, diastolic dysfunction 26.82%, restrictive cardiomyopathy0.60%,andpulmonaryhypertension2.43%.16
TheseresultssuggestthatCVDcouldbepresentinpatients withoutcardiovascularsymptoms,becausenoneofthemhad apreviouspositivecardiovascularevaluation.
In2006,weevaluatedagroupofambulatorypatientswith HIVinfectionwhowereonHAART.Arterialhypertensionwas present in3.26%,type2Diabetesin1.81%,dyslipidemiain 34.05%,smokingin3.96%andobesityin4.71%.
Ofthispopulation,4.16%whoreceivedproteaseinhibitors hadahighcardiovascularriskscoreaccordingwith Framing-hamincomparisonwithpatientswhodidnotreceiveprotease inhibitors,whichhadamoderatecardiovascularriskscorein 12.03%andahighcardiovascularriskscorein0.92%.21
Inthe presentstudy,wedescribed formsofcardiac and non-cardiac vascular alterations, as causes for hospitaliza-tionatRebagliatihospital,anationalreferencehospitalinthe country.Cardiaccauseswerepericardialeffusion,myocardial infarction,myocarditis,bacterialendocarditisandheart fail-ure. None ofthesepatients had cardiovascularrisk factors or were on antiretroviral therapy atthe time of complica-tion.Pericardialeffusionwasthemostfrequentcardiovascular manifestation(4cases).Studyofthepericardialfluidwasnot performedaccordingwiththehospitalprotocols.
Pericardialeffusion inpatientswithHIV infection could berelatedwithinfectionsbyopportunisticagentsor malig-nantneoplasms,butmorefrequentlytheetiologyisunknown. Additionally,pericardialeffusioncouldspontaneouslyresolve inmorethan42%,7–9,16–18consideringthatAIDSpatientswith
pericardialeffusionhaveanannualincidenceofcardiac tam-ponadeof9%,andthat1%ofpatientswithAIDS,annually developthismedicalcondition.16
Weidentifiedthreecasesofmyocardialinfarction,being withSTelevationintwocasesandwithnoSTelevationinone case.STelevationmyocardialinfarctionhadmorethantwo cardiovascularriskfactors(dyslipidemiaandsmoking; hyper-tension,type2diabetes,dyslipidemiaandsmoking)anddid notreceivefibrinolyticsorcoronaryangioplastyfortheacute phase,despitehavingformalindicationstoreceivethem.One patientwithSTelevationmyocardialinfarctiondiedfrom sud-den cardiac deaththree monthsafterdischarge. Moreover, therewas nocaseofmyocardial infarctionassociatedwith pericardialeffusion.
The relationship between viral infections and coronary artery disease hasnot yetbeen fully established. Potential mechanisms by which HIV virus could damage coronary
arteries include the activation of cytokines and adhesion molecules,andsomealterationsofclassItissue histocom-patibilitymoleculesinthesurfaceofsmoothmusclecells.11
However, in the last decades, there were reported cases of acute coronary syndromes (unstable angina or myocar-dial infarction) in patients with HIV infection who were on antiretroviral therapy. Patients with additionalrisk fac-tors, like arterial hypertension, type 2 diabetes, smoking, or hyperhomocysteinemia could have an increased risk to developacutecoronarysyndromesorcerebrovasculardisease, becauseofacceleratedatherosclerosis.16–19
Wefoundtwocasesofmyocarditis,onecaseofheart fail-ure,andanothercaseofbacterialendocarditis.Onecaseof myocarditiswasdiagnosedinthedebutofHIVinfectionand theothercasewasayoungwomanwithlessthantwoyears ofHIVdiagnosis.Thecaseofheartfailurewasdiagnosedina patientwithpreviousmitralvalveinvolvement,andthecase ofbacterialendocarditiswasapatientwithoutprevious car-diacdisease,whoreceivedempiricalantibiotictherapywith goodresponse.
The rate of bacterial endocarditis in patients with HIV infectionissimilartoothergroupsofrisk,likeIVdrugusers. The prevalence varies from 6.3% to 34% in patients with HIVinfection,whoarealsoIVdrugusers.7,8 Itispossibleto
findcasesofnon-bacterialthromboticendocarditis (maran-ticendocarditis),andthisispresentin3–5%ofAIDSpatients, mainlyinthosewithwastingsyndrome.18,19
Cardiac involvementin HIV-infected patients was more frequently present inAIDS patients. Ithas been published that pericardial effusion and myocarditis could be present inlaterstages ofinfection.Onthe other hand,myocardial infarction,alwayssevere,couldbepresentinevery stageof disease.1,2,18–20
Inourreport,wedescribed somecasesofvascular non-cardiacdisease,likesiccasesofdeep veinthrombosis,five casesofcerebrovascular disease,three casesofpulmonary hypertension,and onecaseofpulmonaryembolism.All of thedeepveinthrombosiscasesreceivedantiretroviral ther-apy,andthreeofthemreceivedproteaseinhibitoragents.We knowthatsomeantiretroviralagents,likeproteaseinhibitors induceinsulinresistance,andthenanincreaseof sympathet-icalactivitywithsodiumretention and subsequentarterial hypertension. Other reports indicated that elevated blood pressurecouldberelatedtolipodistrophyandothermetabolic disorders, especially inpatients with hypertriglicerydemia. Moreover,patientswithHIVinfectionthatdevelopfat distri-bution,couldhavecoagulationdisorderslikeincreasedlevels offibrinogen,D-dimer,inhibitorofplasminogenactivator,and decreasedlevelsofSprotein.Theseabnormalitieshadbeen associatedwithbotharterialandvenousthrombosis.10–15
Allcaseswithcerebrovasculardiseasewereischemicand affected individuals below60 years of age (mean age 44.8 years).Fourofthem,wereonantiretroviraltherapy(twoon proteaseinhibitors).Onlyoneofthemhadtype2diabetesas acardiovascularriskfactor.
BraininfarctionorhemorrhageasmanifestationsofHIV infectionhasbeenlessstudied.Morerecentseriesofpatients, describedagreaterproportionofcaseswithbraininfarction (90–95%ofcases)comparedtohemorrhage(5–10%ofcases). Inbraininfarctions,thecauseisfoundinmostpatients,and
disorders ofcoagulations arecommon.DeficiencyinS pro-tein,increasedlevelsofIgGanti-phospholipidantibodies,and anti-cardiolipinantibodieshavebeendescribed.Mostofthe patientsinthisserieshadlowerthan500CD4cells/UL.10–15
Three cases had pulmonary hypertension not associ-atedwithcardiac orpulmonarydisease.Onecasereceived antiretroviral therapywithoutproteaseinhibitors. The inci-dence of pulmonary hypertension associated with HIV infection isapproximately 1/200, amuchgreater incidence thanintheoverallpopulation,whichis1/200,000.This clin-icalentityhadbeenrelatedwiththepresenceofpulmonary infections,IVdrugabuse,factorVIIItransfusioninhemophilic patients, venous thromboembolism, heart failure, and the presenceofHLA-D26andHLA-DR52.10–15
Vascular non-cardiac alterations in our case-series was morefrequentlyobservedthancardiacalterations,andwere associated with early stages of infection. In this report, weevaluatedvascularcardiacornon-cardiacatherosclerotic complications,welldefinedandpresentedinclinicalstudies ascardiovascularendpoints.However,itispossibletodetect subclinical atherosclerosismeasuring carotidintima-media thickening(CIMT)orendothelialfunctionusingflowmediated brachialarteryvasodilation.15
Compared to the pre-HAART era the number ofdeaths has declinedall overthe worldafterHAART use. Thishad been confirmed by some epidemiological studies, like the analysis of some centers controlled by US Department of Defense.Then,987deathsinthepre-HAARTerawere regis-tered,comparedto159deathsinearly-HAART,and78deaths inwell-establishedHAARTera(p<0.01).Ontheotherhand, therehasbeenanincreaseofdeathsnotrelatedtoHIV infec-tion by itself,and anincrease in mortality due to cardiac involvement(22%vs.8%).Inthiscaseregistryinparticular, casesbetween1990and2003wereincludedandHAARTwas initiatedin1997.14
Inourstudy,therewerethreecases(11.53%)ofdeathsfor CVD.Onepatientdiedduetoamassivecerebrovascular dis-easeintheterritoryofmiddlecerebralartery,anotherdueto asuddencardiacasacomplicationofmyocardialinfarction, andthethirdpatientduetopericardialeffusioninaseverely immunosuppressedcase.
IntheINSERM registryinFrance,thecausesofdeathin patientswithHIVinfectionin2005werecomparedtoa pre-viousevaluationperformedin2000.Thepercentageofdeath relatedtoAIDSdeclinedfrom47%to36%.However,therewas anincreaseofthreecausesofdeath:neoplasticdiseases,liver diseases,andCVD.13
ThenumberofhospitalizationsinpersonslivingwithHIV in the HAART era isnot well known. However, the hospi-talizationsbetween2001and2008wereevaluatedin11,645 individualswhoreceivedattentioninUSclinics.Inthisstudy, thehospitalizationsforAIDS-relateddiseasesdeclinedfrom 6.7to2.7per100-persons/year,andtheAIDS-defining infec-tious diseases, psychiatric, or hepatic/CVD were stable or diminished.11
Some demographic factors had been studied in 91,343 admissionsinUSbetween2000and2004.Inthisreport,the mean agewasbetween41and44yearsandthenumberof diagnosisincreasedfrom6(2000)to7.4(2004),andthetotal numberofhospitalizationsreducedby39%.12
InLatin America,aftera carefulreviewinbibliographic databases(IndexMedicus/Medline,Scopus,ScienceCitation IndexandSciELO),wedidnotfindstudiesrelatedto cardio-vascularcausesofhospitalizationinHIVpatients.Therefore, ourstudy,inspiteofbeingdescriptiveandconductedina sin-glecenter,isrelevantgiventhefactitdescribesforthefirst time,cardiovasculareventsashospitalizationcausesinHIV patients.
Ithas been estimatedthat the number of cardiovascu-larormetaboliccomplicationsinpatientsinfectedwithHIV willprogressivelyincrease,asresultoftheincreasein life-expectancy.For2015,itisestimatedthatmorethanhalfof theinfectedpatientswillbeover50yearsofageintheUS, andallovertheworldtherewillbeincreasednumberofcases withaccesstoantiretroviraltherapy.10–15
Finally,inourstudy,wefoundagroupofpatients hospital-izedduetoCVD,withanapproximatefrequencyofoneortwo casesperyear.Wefirstlydescribedagroupofvascularcardiac andnon-cardiacdiseasesthatpromptedhospitalization HIV-infectedpatientsindifferentstagesofthedisease.According toourdata,thepresenceofmoreadvanced immunosuppres-sioncould beassociatedwith higherprobability ofcardiac alterations. Further analytic studies in our country and at regionalsettingsarewarranted.
Funding
Self-funded.
Conflict
of
interest
Theauthorsdeclarenoconflictsofinterest.
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