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HospitalizationRatesandCausesamongPersonswithHIVintheUSandCanada,2005–
2015
ThibautDavy-Mendez,PhD,1,2SoniaNapravnik,PhD,1,,MPH,3KeriN.
Althoff,PhD,3,,MD,MPH,3,,MD,3,,
MD,MAS,FACP,FIDSA,,PhD,MPH,,MB,ChB,MSc,7
,MD,MPH,,MD,9RonaldJ.***,PhD,10JonathanA.
91112Downloadedfrom-article/doi/
Colasanti,MD,MSPH,,MD,,MD,MSPH,
,MD,MSC,13NiGustiAyuNanditha,BSc,14KateBuchacz,PhD,15JunLi,
MD,PhD,,PhD,MHS,,MD,PhD,4AnkNijhawan,
MD,16DavidvanDuin,MD,PhD,,MD,1,,MD,1,2StephenA.
Berry,MD,PhD,4fortheNorthAmericanAIDSCohortCollaborationonResearchand
DesignofIeDEA
1GillingsSchoolofGlobalPublicHealth,UniversityofNorthCarolinaatChapelHill,Chapel
Hill,NC,USA
2SchoolofMedicine,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,USA
3BloombergSchoolofPublicHealth,JohnsHopkinsUniversity,Baltimore,MD,USA
4SchoolofMedicine,JohnsHopkinsUniversity,Baltimore,MD,USA
5KaiserPermanenteMid-AtlanticPermanenteResearchInstitute,Rockville,MD,USA
6KaiserPermanenteNorthernCalifornia,Oakland,CA,USA
7SouthernAlbertaHIVClinic,Calgary,Alberta,Canada
8SchoolofMedicine,UniversityofWashington,Seattle,WA,USA
9SchoolofMedicine,EmoryUniversity,Atlanta,GA,USA
,HarvardUniversity,Boston,MA,USA
11SchoolofMedicine,VanderbiltUniversity,Nashville,TN,USA
12SchoolofMedicine,UniversityofCaliforniaSanDiego,SanDiego,CA,USA
13
SchoolofMedicine,UniAcceptedManuscriptversityCentraldelCaribe,Bayamon,PuertoRico,USA
14FacultyofMedicine,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada
15DivisionofHIV/AIDSPrevention,CentersforDiseaseControlandPrevention,Atlanta,
GA,USA
16UniversityofTexasSouthwesternMedicalCenter,Dallas,TX,USA
PublishedbyOxfordUniversityPressfortheInfectiousDiseasesSocietyofAmerica2020.
Thisworkiswrittenby(a)USGovernmentemployee(s)andisinthepublicdomaininthe
:.
Summary:From2005to2015,insixUSandCanadianclinicalcohortsofpersonswithHIV
withincreasingage,viralsuppression,andCD4counts,unadjustedhospitalizationrates
decreasedoverallandformostcauses.
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AcceptedManuscript:.
ABSTRACT
Background:Toassessthepossibleimpactofantiretroviraltherapyimprovements,aging,
andcomorbidities,weexaminedtrendsinall-causeandcause-specifichospitalizationrates
amongpersonswithHIV(PWH)from2005to2015.
Methods:Insixclinicalcohorts,wefollowedPWHincare(≥1outpatientCD4countorHIVDownloadedfrom-article/doi/
viralload[VL]every12months)andcategorizedICDcodesofprimarydischargediagnoses
hospitalizationrateratiosforcalendartimetrends,adjustedfordemographics,HIVrisk
factor,andannually-updatedage,CD4,andVL.
Results:Among28057patients(125724person-years),from2005to2015,themedian
CD4increasedfrom389to580cells/µLandvirologicsuppressionfrom55%to85%of
--
yearsin2005(95%-)(-).Unadjustedratesdecreased
-cause,cardiovascular,
andAIDS-definingconditions,increasedfornon-AIDS-defininginfection,andwerestablefor
mostothercategories.
Conclusions:AmongPWHwithincreasingCD4countsandviralsuppression,unadjusted
hospitalizationratesdecreasedforall-causeandmostcause-specifichospitalizations,
despitethepotentialeffectsofaging,comorbidities,andcumulativeexposuretoHIVand
antiretrovirals.
AcceptedManuscript
Keywords:HIV;hospitalization;cohortstudies
:.
INTRODUCTION
Antiretroviraltreatment(ART)forHIVinfectionhaschangedsubstantiallyoverthelasttwo
-2000s,theFDAapprovedthesecond-generationproteaseinhibitors
(PIs)atazanaviranddarunavir,anefavirenz-containingsingle-tabletregimen,andanew
classofdrugs,integrasestrandtransferinhibitors(INSTIs)[1].Thesenewregimens
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providedpersonswithHIV(PWH)withsaferandmoreeffectiveARToptions,generallywith
,HIVtreatment
guidelinesrecommendedARTinitiationathigherCD4cellcountsandeventuallyforallPWH
[1].Together,thesechangeshaveresultedinsubstantialimprovementsinviralsuppression
intheUSandCanada[2,3].LifeexpectancyforPWHinthisregionisnowapproachingthat
ofthegeneralpopulation,andalmostone-halfofPWHareover50yearsofage[4-6].
Despitetheseimprovements,PWHexperienceahighburdenofseverenon-AIDS
comorbidities,suchascardiovascular,renal,andliverdiseasesandmalignancies[7-10].
Cumulativeexposuretomoretoxic,olderantiretroviraldrugsandtouncontrolledviremia
leadingtochronicinflammationmaycontributetotheincidenceofcomorbidities[11].In
addition,ahighprevalenceofat-riskbehaviors,suchassmokingandsubstanceuse,and
clinicalriskfactors,suchashypertensionanddyslipidemia,putPWHatriskofdeveloping
comorbidconditions[12,13].
Hospitalizationsprovideanimportantclinicalendpointforexaminingmorbiditytrendsamong
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ratesintheUSandCanada,particularlyforAIDS-definingconditions[14,15].Inthe2000s,
somestudiesreportedacontinueddeclineinall-causehospitalizationrates,whileothers
showedstableorincreasingage-adjustedhospitalizationratesforcardiovascular,
pulmonary,andrenalconditions[14-17].Morerecenttrendsinhospitalizationratesand:.
causesamongNorthAmericanPWHhavebeenwell-described,withstudieslimitedto
smallergeographicareasorpopulationssuchasveterans[18-20].Olderageandincreasing
prevalenceofchronicconditionscouldcontributetomorefrequenthospitalizations,while
hospitalizationmayinformhealthcarepolicyandclinicaleffortstomanagecomorbiditiesin
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,weexaminedtrendsinhospitalizationratesbetween
2005and2015amongPWHinclinicalcareintheUSandCanada.
METHODS
Studypopulationandfollow-up
DataforthisstudycomefromtheNorthAmericanAIDSCohortCollaborationonResearch
andDesign(NA-ACCORD),aconsortiumofcohortsfollowingPWHwhoarelinkedtocare
(≥2visitsina12-monthperiod)[21].Weincludedsixclinicalcohorts(fiveintheUS,onein
Canada)thatcollecteddataonhospitalizationsfromelectronichealthrecordsintheir
medicalsystemfortheperiod2005–2015,includingdischargediagnosisInternational
ClassificationofDiseases(ICD)(IRBs)approved
prospectivedatacollection,andtheUniversityofNorthCarolinaIRBapprovedthis
secondarydataanalysis.
Weincludedpatients≥18yearsoldincarebetween2005and2015,definedasatleastone
outpatientCD4countorHIVviralload(VL)
person-timefromcohortentryor1January2005,whicheveroccurredlater,anduntildeath
or31December2015,-timewascensoredatlosstofollow-
up(LTFU),definedas12monthswithnooutpatientCD4countorVL,butpatients
contributedadditionalperson-timeiftheyre-enteredHIVcare,definedasanoutpatientCD4
-timewasdividedintocalendaryearsforanalysis,allowingpatientsto:.
contributepartiallytoyearswhentheirperson-
countedasperson-timeatrisk.
Studymeasures
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Annualhospitalizationrateswerecalculatedasthenumberofhospitalizationsdividedbythe
person-timeatriskineachcalendaryear,forall-causeandcause-specifichospitalizations.
-day
dischargewerenotcountedasoutcomes,becausethesearerareeventsandcouldnotbe
distinguishedfromoutpatientprocedures().
ClassificationsSoftware(CCS;AgencyforHealthcareResearchandQuality)tocategorize
ICD,NinthRevision,ClinicalModification(ICD-9-CM)codes[22].WemodifiedtheCCSto
classifyAIDS-definingillnessesasaseparatecategoryandreassignallotherinfectionsfrom
organsystemcategoriesintoa“non-AIDS-defininginfection”category[17].Usinga
previouslyvalidatedapproach,iftheprimarydiagnosiswasanICD-9-CMcodeforHIV
infectionorchronichepatitisCvirusinfection,weassignedthenexthighest-rankedICD-9-
CMcodeastheprimarydiagnosis[23].WeconvertedICD,TenthRevisioncodes(11%of
hospitalizations,including9%inCanadaand2%intheUS)toICD-9-CMusingGeneral
EquivalenceMappingsfromtheCentersforMedicareandMedicaidServicesandmanual
(N=206,<1%)wereAcceptedManuscript
includedinall-,a
physiciangroupedICD-9-CMcodesintoclinicallymeaningfulgroups,aspreviously
published[17].
:.
CovariatesincludedNA-ACCORDcohort,gender,race/ethnicity,HIVriskfactor,and
annually-updatedage,CD4count,(<40,40–49,
50–59,≥60years),CD4count(<50,50–200,201–350,351–500,>500cells/µL),andVL
(<400,≥400copies/mL,thehighestlowerlimitofquantification(LLQ)ofassaysusedduring
thestudyperiod).Foreachcalendaryearofanalysis,weusedtheearliestCD4countand
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(9%ofperson-years),weusedthe
earliestmeasurementinthelastsixmonthsofthepreviousyearorthefirstsixmonthsofthe
-yearsstillmissingCD4countorVL(3%)wereexcludedfrom
restrictedtocisgenderwomenaged<50years.
Statisticalanalysis
Unadjustedannualrateswereplottedforall-causehospitalizationsandthetenmost
variablesthatchangedsubstantiallyoverthestudyperiod:age,CD4count,
evaluatedthisapproachbystandardizingratesforall-causehospitalizationsandthemost
commondiagnosticcategorytoeachcovariate,andvisuallycomparingstandardizedto
().
WeusedPoissonregressionmodelstoestimateunadjustedandadjustedincidencerateAcceptedManuscript
ratios(IRR)ofhospitalizationassessinglinearcalendartimetrends,withgeneralized
estimatingequationswithanindependentcorrelationmatrixtoaccountforpatients
change,-yearincreasewasreportedasa-5%annualrate
-:.
adjustedmodelsalsoincludedage,CD4count,
-sided,and<
conductedfoursetsofsensitivityanalyses:(1)usingsixor18monthstodefineLTFU;(2)
usingrestrictedquadraticsplinestoadjustforageandCD4count;(3)usingnegative
binomialmodelstoaccountforpossibleoverdispersion;and(4)adjustingforannually-
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