早期治疗获益与风险的平衡(英文)

EarlyDiagnosisandTreatmentofHIVInfectionBenefitsIndividualsandSocietyRealityofcurrentstatusofthe

globalHIVepidemicEveryyear2.5millionnewHIVinfections1out7(357,000)occurinAsia/PacificregionNeedle-exchangeiseffectiveNovelpreventiontechniquesforsexualtransmissionareneededtosupplementeducation,condoms,andbehavioralchangeInternationalHIVmanagementguidelinesbasedonscientificevidenceBetterhealthoutcomesareachievedwhenHIV-infectedindividualsareidentifiedsoonafterinfection(higherCD4counts);immediatelyconnectedtolong-termhealthcare;andcARTisinitiatedassoonaspossibleWhytreatingearlierbenefitspatientsBiologicalplausibilityIncreasedhealthfulsurvivalReduceTBincidenceAvoidimmunereconstitutionsyndromeImportantcauseoftreatment-relatedmorbidityandmortalityiftreatmentisstartedlate(lowerCD4count)IncreasedhealthfulsurvivalLifeexpectancyissimilartothatofthenon-HIV-infectedpeopleifcARTisstartedearlyenoughtoincreaseandmaintainCD4+cellcountabove500cells/mm3VanSighemA,etal.AIDS2010;24:1527-35.RodgerAJ,etal.AIDS2013;27:973-9.6cART:virologicandimmunologicresponsePercentage<quantificationlimitHIV-RNAassayandCD4cellcountchangeafterstartcARTRiskofdeathandcertaincomplications

“notthoughttobeHIV-associated”:D.A.D.ElSadrW,etal.NEnglJMed2007100WeberR,etal.12thCROI(2005).Abst.595WeberR,etal.ArchInternMed,2006D’ArminioMonforte,etal.14thCROI,2007Cause-specificmortalityassociatedwithmostrecentCD4count>5000.11.010<5050–99100–199200–349350–499CD4+(cells/mm3)RROverallHIVCancerCardiacLiver>MonthsART0-33-66-1212-2424-3605101520253035TBincidencerateTBIncidenceafterInitiationofHAARTcases/100pysLawn,Myers,Edwards,Bekker,Wood.AIDS2009Whystartearly?:

Population

healthbenefitsCurvestheepidemicSocietalbenefitsThosewhowentbefore…BlowerSM,etal.Ataleoftwofutures.Science2000;650-4..Velasco–HernandezJX,etal.CouldwidespreaduseofcombinationantiretroviraltherapyeradicateHIVepidemics?LancetInfectDis2002;2:487-93.LawMG,etal.ModellingtheeffectofcombinationantiretroviraltreatmentsonHIVincidence.AIDS2001;15:1287-94.GranichR,etal.Lancet2010Breakthroughoftheyear2011TransmissionduringtherapyStartingantiretroviraltherapyathigherCD4countsresultsin96%reductionofHIVtransmissionStartatCD4<250vsstartatCD4of350–550Clinicalbenefitstopatients41%reductioninopportunisticinfectionsandmortalityCohenetal.NewEnglJMed2011HeterosexualHIVtransmissionafterinitiationofantiretroviraltherapy(DonnellDetal.Lancet2010)Onlyoneof103genetically-linkedHIVtransmissionsfromanindividualwhohadstartedART.Transmissionrate0.37per100personyearsvs.2.24inthosewhohadnotstartedART:a92%reduction.Arewealreadyseeingabenefitoftreatment?Source:UNAIDSestimates

TasP:isitgoingtobeeasy?

NO

GardnerEMetal.ClinInfectDis2011;52:793-800.

TasP:isitgoingtobeenough?

ItisclearthatTasPshouldbescaledupinconjunctionwithothereffectiveHIVpreventioninterventions.

ButitisalsoclearthatTasPisanessentialcomponentofthepreventionpackageandshouldberolledoutasexpeditiouslyaspossible.

TasP:maybenotenough,butcritical!ThetruthofthematteristhatvirtuallyallHIV-infectedindividualsneedtobetreatedanyhowfortheirownhealth.

Itisbesttodothisinawaythatmaximizesbothindividualandpublichealthbenefits:

-whichmeansasearlyaspossible!

TasP:amisleadingname?Earliertreatment?WHOrecommendstostarttreatmentataCD4<500cells/µlPriorityshouldbegiventothosewithadvanceddiseaseorCD4<350cells/µlWHO,HIVtreatmentandpreventionguidelines2013Earliertreatment?WHOrecommendstostarttreatmentataCD4<500cells/µlPriorityshouldbegiventothosewithadvanceddiseaseorCD4<350cells/µlCouldearliertreatmentleadtomoreresistanceinthepopulationandaffectfututetreatmentsucces?ObjectiveCanthebenefitsofearlierantiretroviraldrugtreatmentbeoffsetbyincreaseddrugresistance?CurrentstatusofdrugresistancePredictedchangeinepidemiologyresistanceafterimplementationofearlytreatmentStrategiestoreducedrugresistanceDrugresistanceMeta-analysesreportthattransmitteddrugresistanceisincreasingin“resource-limited”settingsFrentzetal.AIDSreview2012,Guptaetal.Lancet2012DrugresistanceMeta-analysesreportthattransmitteddrugresistanceisincreasingin“resource-limited”settingsIncreasedaccesstoantiretroviraldrugsFrentzetal.AIDSreview2012,Guptaetal.Lancet2012DrugresistanceMeta-analysesreportthattransmitteddrugresistanceisincreasingin“resource-limitedsettings”IncreasedaccesstoantiretroviraldrugsNosystemicresultsfromAsiadueheterogeneitybetweencountriesLargestincreaseinEast-Africa(29%peryear)PredominantlyNNRTIFrentzetal.AIDSreview2012,Guptaetal.Lancet2012AIDS(2013,27:)MathematicalmodellingStudyingimpactofearliertreatmentondrugresistancewillrequireepidemiologicalfollow-upstudyTime-consumingExpensiveMathematicalmodellingmaybehelpfulKampala,UgandaDatafromPASER–PharmAccessDrugresistanceinIndividualsstartingtreatmentIndividualswhousedtreatment

for1or2yearsHamersLancetInfDis2011,HamersLancetInfDis2012Kampala,UgandaTransmissionofresistance8.6%Acquiredresistance(1y)Zidovudine-basedregimen10%Tenofovir-basedregimen6%DatafromPASER–PharmAccessDrugresistanceinIndividualsstartingtreatmentIndividualswhousedtreatment

for1or2yearsHamersLancetInfDis2011,HamersLancetInfDis2012DruguseDrugsthatwereusedZidovudine,lamivudine,NNRTITenofovir,emtricitabine/lamivudine,NNRTISecondlinebasedonboostedproteaseinhibitorsClassificationofresistanceAntiretroviralClassClassificationZidovudineNRTITAMLamivudineNRTIM184VTenofovirNRTIK65REfavirenz,nevirapineNNRTINNRTILopinavirProteaseinhibitorPIReversiontowild-typewasincluded,rangesfromweeksforM184Vto

yearsforNNRTIresistanceTransmittedDrugResistancePrevalenceNicholsetal.AIDS2013TransmitteddrugresistancebydrugclassormutationNicholsetal.AIDS2013Soresistanceincreases…ButatthesametimemanyinfectionswerepreventedOver10year,comparedtoaCD4<200CD4<350,12.6%infectionsavertedCD4<500,28.8%infectionsavertedPreventionversusResistanceNicholsetal.AIDS2013StrategiestoreducedrugresistanceCanwelimitdrugresistance?ViralloadmonitoringSecond-linetreatmentGenotypingbeforestartoftreatment1.ViralloadmonitoringViralloadmonitoringallowstoidentifyvirologicalfailureinatimelymannerAdherencecounselingSwitchtoalternativetreatmentViralloadmonitoringGuptaetal.LancetInfect.Diseases2009ViralloadWHOrecommendsviralloadmonitoring6monthsafterstarttreatmentEvery12monthsthereafterWHO.Consolidatedtreatmentandpreventionguidelines.20132.Increasingaccessto2ndlineBoostedproteaseinhibitors,havecomparedtoNNRTI’s,ahighgeneticbarrierforresistanceNumberofmutationsrequiredtoovercomedrugselectivepressureDrugresistanceisthereforelesscommonwithproteaseinhibitorsIncreasesecond-lineModellingstudyinKampala,Uganda:Only33-50%ofpatientswithcontinuedfailureonfirst-linemakeitontosecondlineIncreaseto80-100%?Nicholsetal.AIDS2013Increasingaccesstosecond-lineNicholsetal.AIDS20133.BaselinegenotypingResistancetesttoidentifydrugresistanceassociatedmutationsbeforestartoftreatmentTransmissionofdrugresistanceisassociatedwithincreasedriskofvirologicalfailureDrugresistanceWittkopetal.Lancetinfectiousdiseases2011BaselinegenotypingOptimizetreatmentbasedonresultsfrombaselinegenotypingOnlywhenalternativesareavailable2ndlineButwhichstrategyisthebest?Butwhichstrategyisthebest?StrategyReductionTDRInfectionsavertedViralloadeverysixmonths-3.3%32Increasesecondline-11%407Baselinegenotyping-0.5%18Over40yearsCD4<500StrategyReductionTDRInfectionsavertedViralloadeverysixmonths-3.3%32Increasesecondline-11%407Baselinegenotyping-0.5%18Butwhichstrategyisthebest?ViralloadmonitoringatleastonceayearIsresistanceunavoidable?Inmyviewresistancewillalwaysbean