ACTHIV 2018: A State-of-the-Science Conference for Frontline … · 2019-03-12 · Study Year Population N (HIV) Primary Result Effect Size Klein 2002 Kaiser 4159 ↑ MI and CHD in

ACTHIV2018:AState-of-the-ScienceConferenceforFrontlineHealthProfessionals

HowtoComplywithASCVDGuidelinesandHIVthrombosisRisk

Reduction

VirginiaA.TriantMassachusettsGeneralHospital

HarvardMedicalSchool

LearningObjectivesUponcompletionofthispresentation,learnersshouldbebetterableto:

• DescribethecurrentdataonepidemiologyandmechanismofCVDinHIV

• ApplybestpracticesforpredictingcardiovascularriskinHIV

FacultyandPlanningCommitteeDisclosuresPleaseconsultyourprogrambook.

• Nodisclosures.• Therewillbenooff-label/investigationalusesdiscussedinthispresentation.

Outline

• EpidemiologyofHIVandCVD• PathophysiologyofHIVandCVD

– Roleoftraditionalriskfactors– RoleofART– Roleofinflammation/immuneactivation

• ManagementofCVDinHIV– CVDriskprediction– CVDprevention

• Novelriskfactors• Traditionalriskfactors

Outline





HIVPatientsareAgingandFaceIncreasedNCDRates

• Predictedburdenofnon-communicablediseases(NCDs)inHIVpatientsmodeledfor2010-2030

• IncreasingproportionwithmoreNCDsovertime

• NCDsinclude– Cardiovasculardisease

(hypertension,hypercholesterolemia,myocardialinfarction,stroke)

– Diabetes– Chronickidneydisease– Osteoporosis– Non-AIDSmalignancies

SmitLancetID2015.

Non-CommunicableDiseaseComplicationsinHIV

SchoutenCID2014.

• IncreasedNCDratesarenotexplainedbyagealone• Foragivenagegroup,HIVpatientshavehigherburdenofNCDs• NCDsincludeHTN,MI,PAD,CVA,angina,DM2,COPD,CKD,non-AIDScancer,

fracture/osteoporosis

http://www.heart.org/HEARTORG/Conditions/More/HIVandYourHeart/HIV-and-Your-Heart_UCM_313033_SubHomePage.jsp#;http://learn.heart.org/ihtml/application/student/interface.heart2/hiv.html.AccessedDecember8,2011.http://www.nytimes.com/2012/06/19/health/heart-attacks-are-much-more-frequent-in-hiv-patients.html.Accessed9/24/2015.

HeartdiseaseisincreasedinHIVandincreasinglyrecognizedasaclinicaland

publichealthpriority

HIVandRiskofAcuteMyocardialInfarction

Study Year Population N (HIV) Primary Result Effect Size

Klein 2002 Kaiser 4159 ↑ MI and CHD in HIV vs. control 1.5 (MI) 1.7 (CHD)

Currier 2003 CA Medicaid 28513 ↑ CHD in HIV (age 18-33) vs. control

2.06

Triant 2007 Partners 3851 ↑ MI in HIV vs. control 1.75

Obel 2007 Danish cohort 3953 ↑ CHD in HIV (on ART) vs. control

2.12

Lang 2010 FHDH 74958 ↑ MI in HIV vs. 3 populationregistries

1.5

Durand 2011 Quebec 7053 ↑ MI in HIV vs. 4:1 matched control

2.11

Freiberg 2013 VA 27350 ↑ MI in HIV vs. 2:1 matched control

1.48

Silverberg 2014 Kaiser 22081 ↑ MI and CHD in HIV vs. 10:1matched control

1.4

KleinJAIDS2002;CurrierJAIDS2003;TriantJCEM2007;ObelHIVMed2010;LangAIDS2010;DurandJAIDS2011;FreibergJAMAInternMed2013;SilverbergJAIDS2014;GutierrezPLOSONE2017.

HospitalizationRatesbyDiagnosis

• Hospitalizationdatafrom2001to2008from11,645HIV-infectedadultsat4geographicallydiverseUSHIVclinicswithintheHIVResearchNetwork

• CVDadmissionssurpassedAIDS-definingillnessadmission

BerryIAC2010andJAIDS2012;Crum-CianfloneJAIDS2010.

CVD-RelatedMortalityinHIV

MorlatAIDS2014.

• Comparedmortalityfrom2000to2010inFrenchnationalsample• AIDS-relatedmortalitymarkedlydeclined• CVD-relatedmortalityincreased

Outline





ART

CVD

DYSLIPIDEMIA

DIABETES

HYPERTENSION

SMOKING

PathophysiologyofHIV-AssociatedCVD

• Early2000s• IncreasedCVD

riskinHIVinitiallyrecognized

• Riskattributedto:– TraditionalCVD

riskfactors

Early2000sCVDriskdata

2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

TraditionalCVDRiskFactorsinHIV

SmokinginHIV• Highprevalence

– 56%(D:A:D)– 54%(SFGH)– 47%(UScohort)– 69%(French

cohort)• 85%lifetimehistory• Morelifeyearslost

throughsmokingthanthroughHIV

0

5

10

15

20

25

Hypertension Diabetes Dyslipidemia

Diagnosis (By ICD Code)

Rat

e Pe

r 100

Per

sons

TriantJCEM2007;BurkhalterNicotineTobRes2005;Friis-MollerAIDS2003;MamaryAIDSPtCareSTDs2002;GritzNicotineTobRes2004;VittecoqAIDS2003;SavèsCID2003;LifsonAJPH2010;Helleberg,CID2013.

HIV+

HIV-

DyslipidemiainHIV• DistinctivepatternoflowHDLandhighTG• MaybeimpactedbyPIs

ARTDRUGS

ART

CVD

DYSLIPIDEMIA

DIABETES

HYPERTENSION

SMOKING



2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

• Mid-2000s• Emergingdata

onCVDriskwithARTdrugsandclasses

• Riskattributedto:– TraditionalCVD

riskfactors– IndividualART

drugeffects

AMIIncidenceIncreasedwithPIs

• D:A:D- prospectiveobservationalcohortof33,347patients• RelativeriskofAMI1.16peryearARTexposure• PIsbutnotNNRTIsconferredincreasedrisk• Cumulativeexposuretoindinavir(RR1.12peryear)andlopinavir-

ritonavir(RR1.13peryear)associatedwithincreasedriskofAMI• Noincreasedriskobservedwithatazanavir

Friis-MollerNEJM2007.

DarunavirandCVDRisk

• IncreasingCVDriskwithcumulativeexposuretoDRV/rbutnotATV/rinmultivariatemodels• 59%increasedriskCVDper5yearsexposuretoboosteddarunavir• StrengthofassociationsimilartothatofIDVandLPV/rbutnotmodifiedbydyslipidemia• Multiplesensitivityanalysesperformedwithunchangedresults• SuggestspossiblePIclasseffect

– Atazanavirisexception:hyperbilirubinemiaassociatedwithdecreasedCVDrisk• Clinicalimplicationspotentiallysignificantà furtherstudieslikely

Ryometal.Abstract128LB.CROI2017;Marconietal.Abstract127.CROI2017.

AbacavirandMIRiskStudy N Design Effect EffectSize

D:A:D 33347 observationalcohort Yes RR1.90

SMART 2752 observationalRCT Yes HR4.3

GSK 14174 pooledRCTs No RR0.81

STEAL 357 RCT Yes HR0.12(TDF)

Danish 2952 prospectivecohort Yes RR2.00

FHDH 1173 nestedcase-control No OR1.27

VA(original) 19424 observationalcohort No HR1.18/yr

Quebec 7053 nestedcase-control Yes OR1.79

Meta-analysis 9233 28RCTmeta-analysis No RR0.73

FDAMeta-analysis 5028 26RCTmeta-analysis No OR1.02

ALLRT 5056 ACTGRCTs No HR0.7

VA 10931 observationalcohort Yes HR1.48

Sabin Lancet 2008;371:1417-1426; SMART/INSIGHT/DAD AIDS 2008;22:F17-F24; Brothers JAIDS 2009;51:20-28; Martin CID 2009;49:1591-1601; Obel HIV Med 2010;11:130-136; Lang Arch Int Med 2010;170:1228-1238; Bedimo CID 2011;53:84-91; Durand JAIDS 2011;epub; Cruciani AIDS 2011;57:245-53. Ding CROI 2011. Abstract 808; Ribaudo CID 2011;52:929-40; Choi AIDS 2011;25:1289-1298.

AbacavirandMIRiskintheNA-ACCORD

• N=8265NA-ACCORDparticipants

• Recentabacaviruseinprior6monthsassociatedwithincreasedriskofMIafteradjustmentforknownCVDriskfactors– AdjustedHR1.84

• KaplanMeierestimatesfortimefromARTinitiationtofirstmyocardialinfarction,byrecent(withinthelast6months)abacaviruse

Elion et al. JAIDS 2018:epub.

AbacavirandCVDRisk• SeveralstudiesatCROI2018addtoabacavirstory• Plateletfunction

– Mallon(80)– increasedplateletreactivity– Taylor(673)– studiesofplateletdysfunctionwithabcavair(reversalofNO’sinhibitoryeffectonplateletaggregation,enhancedgranulesecretionandplateletactivation)

– Collado-Diaz(674)– pro-thromboticeffectofabacavirdependsonleukocytes

• Increasedcoronaryplaquewithabacavir(692)• ModellingstudyofabacavirreplacementonCVDrisk(692)

Mallonetal.Abstract80.CROI2018;Tayloretal.Abstract673.CROI2018;Collado-Diazetal.Abstract674.CROI2018;Kovarietal.Abstract692.CROI2018;Hsueetal.Abstract692.CROI2018.

CVDRiskPersists…• Persistentlyincreasedrisk

afteraccountingfortraditionalCVDriskfactorsandARTdrugs– Traditionalriskfactorsonly

accountfor10-25%ofriskinlargecohorts

– Persistent40-80%increasedriskinHIV-infectedpatients

• Whatisadditionalcomponentdrivingrisk?

?

ART

TraditionalCVDRiskFactors

ARTDRUGS

ART

CVDIMMUNE

ACTIVATION

INFLAMMATION

DYSLIPIDEMIA

DIABETES

HYPERTENSION

SMOKING

GENETICS



2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

• Riskattributedto:– TraditionalCVDrisk

factors– IndividualARTdrug

effects– Inflammationand

immuneactivation

SMART,InflammationandCVD• SMARTstudyoftreatmentinterruption• PrimaryendpointrecurrentOI/death• IncreasedCVDeventratesindrug

conservation(episodictreatment)vs.viralsuppression(continuoustreatment)group• HR=1.57,P=0.05

• InflammatorymarkersIL-6andd-dimerincreased1monthaftertreatmentinterruptioninSMART

• BaselinehsCRP,IL-6,andd-dimerstronglycorrelatedtooverallmortality

• Suggestsroleforinflammation

El-SadrNEJM2006;PhillipsAIDS2008;KullerPLoS2008.

InflammationandCVD• Extensivedatasupporta

roleforinflammationinHIV-associatedCVDrisk– SMARTstudy– Biomarkersofinflammation

linkedtosurrogatemarkersofCVD

– Vulnerableplaqueandarterialinflammationlinkedtomonocyteactivation

– Clinicalsurrogatesofinflammation(viralload)andimmuneactivation(CD4)linkedtoCVDevents

– STARTstudy

• Aorticarterialinflammation(measuredbytargettobackgroundratioofFDGuptakeinarterialwall)higherinHIVvsnon-HIV

• sCD163,markerofmonocyteactivation,higherinHIVgroupthancomparablenon-HIVcontrolparticipants

• Aorticarterialinflammation(TBR)significantlycorrelatedwithsCD163

DecreasedCD4CountLinkedtoCVD

• CD4<500associatedwithCVDeventsindependentofCVDriskfactorsorART

• CD4<200associatedwithincreasedAMIrisk(OR1.74)

ABC

VL>100000

CD4<200

Smoking

CKD

LipidDMHTN

Non-white

Female

Age/10yrs

DDI

FTCD4T

TDF

NVPATV

NFVSQV

ART Year

0.1 1 10

LichtensteinCID2010;TriantJAIDS2010.

IncreasedHIVRNALinkedtoCVD

• IncreasedHIVviralloadassociatedwithincreasedischemicstrokerisk

• Detectableviralload(>50)associatedwithincreasedAMIrisk(OR1.51)

ChowJAIDS2014;LangCID2012.

DecreasedCD4CountandHIVViremiaIndependentlyIncreaseCVDRisk

FreibergJAMAIM2013.

• AMIriskinVAstudybyCD4andHIVRNAstatus• HIVRNA≥500andCD4<200eachassociatedwithincreasedAMIrisk• AMIriskpersistsinpatientsachievingviralsuppression

– Riskattributedtopersistentinflammation

STARTStudy• StrategicTimingofAntiRetroviral

Treatment(START)study• FirstRCTtoassessratesofevents

includingnon-AIDSbyearly(>500)versusdeferred(<350)ARTinitiation

• Kaplan–Meierestimatesofthecumulativepercentagesofpatientswiththecompositeprimaryendpoint(seriousAIDS-relatedorseriousnon–AIDS-relatedevent)

• Earlytreatmentreducedseriousillness/deathby53%

– 70%riskreductionforAIDSevents– 33%riskreductionfornon-AIDSevents

• ReinforcednetbenefitofearlyARTfromCVDperspective

InsightStartStudyGroupNEJM2015

UNTREATEDHIV

ART

CVDIMMUNE

ACTIVATION

INFLAMMATION DIABETES

HYPERTENSION

SMOKING



2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

• Riskattributedto:– TraditionalCVDrisk

factors– IndividualARTdrug

effects– Inflammationand

immuneactivation– UntreatedHIV DYSLIPIDEMIA

ARTDRUGS

Outline





ChallengesinManagementofHIV-AssociatedCVD

• Understandingofmechanismhasnotyettranslatedintotailoredclinicalinterventions– Areaofintensiveinvestigation

• Currentguidelinesmaybeinadequate– Unclearapplicabilityofgeneralpopulationguidelines– LimitationsofHIV-specificguidelineswithrespecttoCVD

Intervention TraditionalRiskFactors NovelRiskFactors

Statins

ASA

ART

Immunomodulatory agents

Smokingcessation

Diabetesmanagement

HTN management

UNTREATEDHIV

ART

CVDIMMUNE

ACTIVATION


HYPERTENSION

SMOKING

DisconnectofMechanismandPreventioninHIV-AssociatedCVD


2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

DYSLIPIDEMIA

CURRENTCVDPREVENTION

STRATEGIESONLYTARGET

TRADITIONALCVDRISKFACTORS

ARTDRUGS

Outline





ACC/AHACVDRiskGuidelinesAddComplexitytoRiskPredictioninHIV

• NewACC/AHAguidelinesonCVDriskestimationreleasedin2013• NewCVDriskpredictionequationemployed(Pooledcohortsequation)• Reportsofoverestimation ofriskinthegeneralpopulation• ReleaseofnewlongitudinalriskestimatorthatfactorsinCVDriskfactortreatment

GoffCirculation2014;Lloyd-JonesJACC2016.

CVDRiskPredictioninHIV• Riskpredictionalgorithmspredict10-yearriskofdevelopingCVD

forthegeneralpopulation– FraminghamRiskScore– ACC/AHA

• AccuracyofCVDriskpredictionalgorithmsinHIVisunclear• HypothesizedthatexistingCVDriskpredictionalgorithms

underestimate risk– IncorporateonlytraditionalCVDriskfactors– Donotincorporatenovel,HIV-relatedfactors

• In2013ACC/AHAreleasednewCVDriskpredictionalgorithm(PooledCohortsEquations)designedtobeapplicabletoamoregeneralU.S.population.– Initialreportsdemonstratedpossibleoverestimation ofrisk

LawHIVMed2006;MateenNeurology2013;Friis-MollerEurJCardiovascPrevRehabil2010;Friis-MollerEurJPrevCardiol2016;Thompson-PaulCID2016;GoffCirculation2014.

CVDRiskPredictioninHIV• HIV-specificriskpredictionalgorithmdevelopedbyD:A:Dgroupincludes

traditionalCVDriskfactorsplus:– Indinavir,lopinavir/ritonavir,andabacavirexposure– CD4count,cumulativePIandNRTIexposure,andcurrentabacaviruse(updatedmodel)– NotwidespreadclinicaladoptioninU.S.

• EmergingdatasuggesttraditionalCVDriskalgorithmsareinaccurateinHIV• HOPScohort

– Evaluated4riskscoresin2283HIV-infectedindividuals– Nomodelperformedwellforbothcommonmetrics:

• Discrimination(abilitytodistinguishpatientswithandwithoutoutcome)• Calibration(agreementbetweenobservedandpredictedrisk)

– FRS:goodcalibrationbutmoderatediscrimination– ACC/AHAPCEandD:A:D:gooddiscriminationbutmoderatecalibration– SCORE:poordiscriminationandcalibration

• CNICScohort• PartnersHIVcohort

LawHIVMed2006;MateenNeurology2013;Friis-MollerEurJCardiovascPrevRehabil2010;Friis-MollerEurJPrevCardiol2016;Thompson-PaulCID2016.

CVDRiskPredictioninCNICS

FeinsteinJAMACardiology2016

• ACC/AHAPooledCohortsEquationsvalidatedin11288patientsinCNICS• Discrimination(abilitytodistinguishpatientswithandwithoutoutcome)adequate• Calibration(agreementbetweenobservedandpredictedrisk)moderatebutdrivenbywhitemen• Underestimation ofriskdemonstrated:

– Amongblackwomenandmen– Amonglow/moderatepredictedCVDriskgroupswhereclinicaldecisionmakinguncertain

• HIV-specificfactorsdidnotimproveriskprediction

CVDRiskPredictioninPartners

• FRSandACC/AHAriskscoresvalidatedin1272patientsinPartnersHIVCohort• Discrimination(abilitytodistinguishpatientswithandwithoutoutcome)moderate

– cstatistics0.68,0.65inmenand0.66,0.62inwomenforFRSandACC/AHA)• Calibration(agreementbetweenobservedandpredictedrisk)poor

– ReflectsinadequatefitofgeneralpopulationfunctionstoHIV• ObservedriskgreaterthanpredictedriskforACC/AHAinallbut2nd decileformenandalldecilesforwomen• Underestimation ofriskdemonstrated,withdegreeofunderestimationgreater:

– Amongwomen– Amonglow/moderateCVDriskgroupswhereclinicaldecisionmakinguncertain

ACC/AHA:MALES ACC/AHAFEMALES

Triant,CROI2015;Triant,Circulation2018.

CVDRiskPredictioninHIV:Strategies

• EstablishedCVDriskpredictionalgorithmsappeartounderestimateriskinHIV

• OptimizingCVDriskpredictioninHIVwilllikelyrequireincorporatingnovelriskfactorsthatreflectthemechanismofHIV-associatedCVD

Clinicalstrategy• ConsiderusingACC/AHAriskscoreaslowerestimateofrisk

– CurrentalgorithmsdonotaccountforHIV-relatedfactors• Patientsinhigh-riskcategorybyatleastonescore(>7.5%for

ACC/AHAor>10%forFRS)merit:– SuppressiveARTifnotalreadytreated– Strongconsiderationofstatin– AggressiveCVDriskfactorreduction

• Roleforentireclinicalteam(non-prescribers)• Promotionoflifestylemodification

Basedonexpertopinion.

Outline





StatinsinHIV• Statinsareaninterventionthatmayreducebothtraditionalandnovel

CVDriskfactorsinHIV;pleiotropiceffectsinclude:– Lipid-loweringeffects– Anti-inflammatoryeffects

• InHIV,statinshavebeenshownto:– EffectivelylowerLDL

• MaybelesseffectiveinHIVvsnon-HIV– Decreaseimmuneactivation(Tcellandmonocyte)– ContributetoimmunereconstitutionindependentofART– Reducenon-calcifiedplaquevolumeandhigh-riskcoronaryplaquefeatures– SlowprogressionofCCA-IMT– Reduceriskofvirologic failureafterviralsuppressiononART– DecreasemortalityinanHIVobservationalcohort

• YetitremainsunknownwhetherstatinspreventCVDinHIV– OngoingREPRIEVEtrialisaddressingthiscriticalquestion

HadiganCID2001;RiddlerJAMA2003;SilverbergAnnIntMed2009;Funderburg,CROI2014abstract335;EckardJID2014;DrechslerCROI2014abstract308;LoLancetHIV2015;LongeneckerAIDS2016;Drechsler PLOSONE2017;MoorePLoSOne2011.

2013ACC/AHACholesterolGuidelines

• Recommendednewapproachtodeterminestatineligibility(replacedNCEPATP-III)• Statininitiationrecommendedfor4majorbenefitgroups

– ClinicalASCVD– LDL≥190mg/dL– DMage40-75– Estimated10-yearASCVDrisk≥7.5%

• NewACC/AHACVDriskalgorithmusedtoestimate10-yrASCVDrisk• UnclearapplicabilityinHIV

– HIVpatientsexcludedfromRCTsonwhichguidelinesbased– ACC/AHAriskscoremaybeinaccurateinHIV– Statin-ARTdruginteractionsarenotaccountedforinstatinintensityrecommendationswhich

arefixeddose• GuidelinesfailedtorecommendstatinsinmajorityofHIVpatientswithhigh-risk

morphologycoronaryplaqueorwithcarotidplaqueStoneCirculation2014;ZanniAIDS2014;PhanCirc Cardiovasc Imaging2017.

LimitationsofACC/AHACholesterolGuidelinesinHIV

StoneCirculation2014.

FurtherChallengesinApplyingNewCholesterolGuidelinestoHIV

StoneCirculation2014.

Dose-adjustmentinHIV(withPIs)

ContraindicatedinHIV(withPIs)

AwaitingfurtherstudyinHIV

REPRIEVE• ToaddressgapsinknowledgeonstatinsinHIV,theREPRIEVEtrialwas

designedtoaddress:• WhetherstatinspreventCVDinHIV• WhichpatientswithHIVshouldreceiveastatin

• REPRIEVEisthefirstlarge-scalerandomizedclinicaltrialtotestastrategyforpreventingheart-relateddiseaseamongpeoplelivingwithHIV

• REPRIEVEspecificallytargetspatientsatlowtraditionalCVDriskwhowouldnotberecommendedforastatintoassesswhetherstatinsimpactHIV-relatedriskfactorsbeyondlipids

Personalcommunication,Grinspoon2014.

Hypothesis:StatinswillpreventcardiovasculardiseaseinHIV-infectedpatients,particularlyamongthelargegroupwithminimaltraditionalriskandnotmeetingcurrentguidelinesforclinicaluseof

statinsbutatriskforCVDbasedonuniquepathophysiologyofvulnerableplaquemorphologyandinflammation

REPRIEVEStudyDesign• 6500patients

– 4552enrolled• 100+sites

– US/international• Eligibility

– Age>40– NoCVD– Notonstatin– StableART– Notrecommended

forstatinby2013ACC/AHAguidelines

• Tobecompletedmid-2018

Intervention

Clinical Primary Endpoint

TimeScreening

AndConsent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic Primary Endpoint

Coronaryplaque,vascularinflammation,immuneactivation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

Figure 4. Schematic overview of REPRIEVE trial design.

Intervention

Clinical Primary Endpoint

TimeScreening

AndConsent

Asymptomatic HIV+ patients with no history of CVD

Pitavastatin 4mg/dayPlacebo

MICV Death Unstable Angina Arterial Revasc

Secondary Endpoints

Individual components of primary endpoint

All Cause Death

RandomizationR

Incidence/Progression of noncalcified plaque; High-risk plaque

Mechanistic Study

Inflammatory, immunological, metabolic biomarkers

Mechanistic Primary Endpoint

Coronaryplaque,vascularinflammation,immuneactivation

Stroke

Predictors of statin effects

Statin safety and non AIDS comorbidities: DM, Infections, Cancer

All cause death

Figure 4. Schematic overview of REPRIEVE trial design.

Personalcommunication:GrinspoonandFitch2017.

NovelInterventionsTargetingResidualInflammationandImmuneActivation

• ARTtreatmentintensification– Additionofraltegravir didnotimproveendothelialfunctionormarkers

ofTcellactivation• CCR5antagonists - blockHIVco-receptorCCR5

– Maraviroc reducedprogressionofatherosclerosisinmousemodel• Rifaximin – antibioticwithanti-inflammatoryproperties

– MinimallyaffectedmicrobialtranslocationandT-cellactivationinARTimmunenonresponders

• Sevelamer – phosphate-bindingdrug– Didnotreducemicrobialtranslocation/immuneactivationbutdid

improvelipidindices• Mesalamine (5-aminosalicylicacid)– decreasesmucosal

inflammationinUC– DidnotreduceTcellactivationorincreaseCD4count

HatanoJAIDS2012;GandhiJAIDS2012;SteinJAMA2012;JonesBrJPharmacol2011;CiprianiCirculation2013;Tenorio JID2015;SandlerJID2014;Somsouk PLOSONE2014.

NovelInterventionsTargetingResidualInflammationandImmuneActivation

• Pentoxifylline - phosphodiesteraseinhibitor– Didnotimproveendothelialfunctionandunexpectedly increasedinflammatorybiomarker

sTNFRI inuntreatedHIV– Didnotimproveendothelialfunctionandunexpectedlyattenuatedreductionsin

proatherogenic inflammatorybiomarkersinpatientsinitiatingART• Hydroxychloroquine – immunomodulatory/anti-inflammatoryusedinSLEand

GFVD– DidnotreduceTcellactivationandunexpectedlyresultedingreaterCD4declineand

increasedviralreplication• Low-dosemethotrexate

– Recenttrialof176patients– A5314– Nodifferenceinendothelialfunction(assessedbyFMD),inflammatoryorcoagulationmarkers

(hsCRP,IL-10,sCD163,d-dimer,fibrinogen,VCAM,IL-6)– DecreaseinCD4andCD8Tcellactivationwithlow-dosemethotrexate– DecreaseinarterialinflammationbyFDG-PETwithlow-dosemethotrexate

• IL-1β inhibitionwithcanakinumab – monoclonalantibodythatbindsIL-1β andinhibitsIL-6production

– Ongoingtrialassessingendothelialfunction(assessedbybrachialarteryFMD),vascularinflammation(assessedbyFDG-PET/CTscanning),inflammatorymarkers(hsCRP,IL-6,sCD163),D-dimer,T-cell/monocyteactivation,HIVreservoirsize

GuptaPLoSOne2013;GuptaAIDS2016;PatonJAMA2012;HsueCROI2018;Tawakol CROI2018;www.clinicaltrials.gov.

TraditionalCVDRiskFactors:Strategies

SMOKING• Prioritizecessationforall

HIV-infectedsmokers

DYSLIPIDEMIA• Usecurrentguidelinesas

lowerthresholdforstatinprescription

• CheckfastinglipidsasperHIVPrimaryCareGuidelines

• Beawareofstatin-ARTdruginteractions

• AwaitREPRIEVEresults

DIABETES• Checkfastingglucoseor

HbA1CasperHIVPrimaryCareGuidelines

• HbA1CmayunderestimateglycemiainHIV– Considercutoff5.8%

HTN• FollowexistingJNC8(2014

HypertensionGuideline)forgeneralpopulation

FitchAIDS2006;AbergCID2014;LundgrenHIVMed2008;ChobanianHypertension2003;CROI2014abstract769;JamesJAMA2014;FitchAIDS2006;AbergCID2014;LundgrenHIVMed2008;ChobanianHypertension2003;CROI2014abstract769;JamesJAMA2014;EtziAntivirTher2006;TashimaCROI2009abstract148;TorneroJAIDS2009;TreatingTobaccoUseandDependenceDHHS2008.

LifestyleModificationStrategies:RoleoftheClinicalTeam

• IntensivelifestylemodificationimprovesCVDriskindicesinHIV-infectedpatientswithmetabolicsyndrome

• QuittingsmokingdecreasesAMIeventratesinHIV

• IRR3.73<1yearsincequitting• IRR2.07>3yearssincequitting

• ApplyguidelinesforgeneralpopulationtoallHIVsmokers– Routinescreeningintegratedinto

HIVprimarycare– Strong,brief,intensiverepeated

counseling– UnclearwhetherHIV-specific

smokingcessationinterventionsindicated

– Roleforallmembersofclinicalteam

• ConsidersystematicapproachestoidentifyHIV-infectedpatientswhomightbenefitfromlifestylemodification– Counselingandeducation– Linkingtocommunityresources

FitchAIDS2006;Petoumenos HIVMed2011.

ARTandCVDPrevention

• ShiftovertimeinoverallroleofARTinrelationtoCVDriskinHIV• BenefitofARTwithviralsuppressionandimmunereconstitutionthoughtto

outweighpotentialpro-atherogeniceffectsofindividualmedications– CanbeconsideredCVDinterventionfornovelriskfactors

• RoleofARTasbeneficialfromCVDstandpointsupportedbyclinicaltrials– SMARTtrial:continuoustreatmentsuperiortointerruptedtreatment– STARTtrial:earlytreatmentsuperiortodeferredtreatment

• RoleofARTasbeneficialfromCVDstandpointreflectedinHIVtreatmentguidelines– 2010IAS-USAHIVtreatmentguidelines recommendedinitiationofARTspecifically

forpatientswithhighcardiovascularriskregardlessofCD4count– 2012DHHSHIVtreatmentguidelines recommendantiretroviraltherapyforallHIV-

infectedindividuals• TherecommendationtoinitiatetherapyatCD4count>500cells/mm3(BIII)isbasedongrowing

awarenessthatuntreatedHIVinfectionoruncontrolledviremiamaybeassociatedwithdevelopmentofmanynon-AIDSdefiningdiseases,includingcardiovasculardisease (CVD), kidneydisease,liverdisease,neurologiccomplications,andmalignancy

ThompsonJAMA2010;ACCF/AHA/ACPCirculation2009;http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

UNTREATEDHIV

ART

CVDIMMUNE

ACTIVATION


HYPERTENSION

SMOKING

PreventionofHIV-AssociatedCVD


2006SMARTtrial

2007-2008ARTdata

2015STARTtrial

DYSLIPIDEMIATRADITIONALRISKFACTOR

MODIFICATION:STATINSSMOKINGCESSATION

TREATDM/HTNLIFESTYLE

TREATHIV

STATINSNOVELANTI-

INFLAMMATORIESPREVENTCVD

ARTDRUGSSELECTARTBASEDONCVDRISK

ImplicationsandFutureQuestions• SignificantimpactofCVDinHIVpopulationsrelatedtoinflammation• Currenttreatmentandpreventionparadigmsdonotreflectmechanism• Clinicallyrelevantquestions

– HowisCVDriskmostaccuratelyassessedinHIV?– Whatistheroleforstatinsandanti-inflammatory/immunomodulatoryagents

inreducingCVDriskinHIV– HowdoesCVDdifferinHIVpatientsinresource-limitedsettings?– ShouldHIVbeconsideredacardiovascularriskequivalent?

• Recommendedstrategies– TreatHIVtoreduceinflammation,immuneactivationandassociatedCVDrisk– BuildCVDriskassessmentintopractice– ConsiderunderlyingCVDriskwhenselectingspecificARTdrugs– ManagetraditionalCVDriskfactorsaggressively(e.g.smoking)– Engageentireclinicalteamincludingnonprescribers

• IntensityandconsistencyofHIVcareandpatientengagementincareprovideopportunitytopreventandmanagechronicdiseasecomplications

AcknowledgmentsColleagues,collaboratorsandmentors• StevenGrinspoon• JamesMeigs• RalphD’Agostino• JosephMassaro• MichaelSilverberg• DanielKlein• SusanRegan• MosepeleMosepele• ShahinLockman• FeliciaChow• MarkellaZanni• JanetLo• SaraLooby• TomasNeilan• ScottDryden-Peterson• MarkSiedner• KathleenFitch• JacquelineChu

Researchsupportfrom:• NIH/NHLBI• AmericanHeartAssociation• MassachusettsGeneralHospitalExecutive

CommitteeonResearch

Documents

ACTHIV 2018: A State-of-the-Science Conference for Frontline … · 2019-03-12 · Study Year Population N (HIV) Primary Result Effect Size Klein 2002 Kaiser 4159 ↑ MI and CHD in