Strategies to support the COVID-19 response in LMICs
Transcript of Strategies to support the COVID-19 response in LMICs
Therapeutics Landscape for COVID-19 NatashaMubeenChida,MDMSPHAssociateProgramDirector,InfectiousDiseaseFellowshipProgramAssistantProfessor,DivisionofInfectiousDiseasesJohnsHopkinsUniversitySchoolofMedicine
Objectives
• ReviewbiologicalplausibilityofRemdesivirforSARS-CoV-2treatment• ReviewclinicaldataonRemdesivir• ReviewbiologicalplausibilityofHydroxychloroquineforSARS-CoV-2treatment• ReviewclinicaldataonHydroxychloroquine• DiscusscytokinereleasesyndromeinCOVID-19• DiscussuseofantiIL-6blockadeformanagementofCRS• StateongoingclinicaltrialsforRemdesivir,hydroxychloroquine,IL-6blockade
Sample of COVID-19 Therapeutic Landscape
Antivirals ImmuneModulators Other
Baloxavir Anakinra ACEI/ARB
Chloroquine/Hydroxychloroquine ConvalescentPlasma AscorbicAcid
DAS-181 Corticosteroids Azithromycin
Favipiravir IVIG Epoprostenol
Interferon Lenzilumab Indomethacin
Lopinavir/Ritonavir Ruxolitinib Ivermectin
Neuraminidaseinhibitors Sarilumab Niclosamide
Remdesivir Sirolimus Nitazoxanide
Ribavarin Tocilizumab Statins
Umifenovir Acalabrutinib
SARS-CoV-2
LiuC,etal.ACSCentSci.doi:10.1021/acscentsci.0c00272(2020).JiangS,HillyerC,DuL.TrendsImmunoldoi:10.1016/j.it.2020.03.007(2020).
Remdesivir
• 2013Ebolaoutbreak• CDC/USAMRIDD/GileadSciencesidentifiednucleosideleadàprodrug,RDV
• Metabolizedtoactiveform,adenosinenucleosideanalog• InterfereswithRNApolymerase
• Evadesviralexoribonucleaseproofreading• DecreaseinRNAproduction
• Incell/animalmodelsefficaciousinMERS-CoV,SARS-CoV,Marburg,Nipah,more• IVformulation
Remdesivir
WarrenTK,etal.Nature.2016;531(7594):381-5.SheahanTP,etal.SciTranslMed.2017;9(396).
Remdesivir Clinical Data
• ReportofpatientsJan-March-61patientsà53• 40(75%)receivedthefull10-daycourseofRemdesivir• 34(64%)ventilatedatbaseline
• MediandurationofventilationpriortoRemdesivir2days[IQR1-8]
GreinJ,etal.NEnglJMed.doi:10.1056/NEJMoa2007016(2020).
Remdesivir Clinical Data
• 18days• 36(68%)showedimprovementinoxygensupport• 57%ventilatedpatientsextubated
• Mostrecentfollowup• 25(47%)discharged• 7(13%)died
• 6(18%)ofthoseventilated,1(5%)notventilated
GreinJ,etal.NEnglJMed.doi:10.1056/NEJMoa2007016(2020).
Remdesivir Clinical Data
• 23%seriousadverseevents
GreinJ,etal.NEnglJMed.doi:10.1056/NEJMoa2007016(2020).
Lopinavir/Ritonavir
• In-vitroactivityagainstSARs-CoV,MERS-CoV• Hypothesis:inhibitionofSARs/MERSprotease
• BenefitinretrospectivestudiesinSARs-CoV• SomeinvitrodataSARS-CoV-2,butEC50muchhigherthanlevelsreachedinHIVdosing
• HIVproteasedifferentproteasefamily• OptimizedtofitinaspecificpartofthecatalyticsiteofHIVprotease,absentincoronaviruses• SomebenefitinanimalstudiesMERS-CoV
• WidelyusedinChina• Numerousretrospectivestudies
LiG,DeClercqE.NatRevDrugDiscov.2020;19(3):149-150.,YaoTT,etal.JMedVirol.doi:10.1002/jmv.2572(2020).,JiangS,HillyerC,DuL.TrendsImmunoldoi:10.1016/j.it.2020.03.007(2020).,ChoyKTetal.AntiviralRes.doi:10.1016/j.antiviral.2020.104786(2020).
Lopinavir/ritonavir
Lopinavir/ritonavir Data
CaoB,etal.NEnglJMed.doi:10.1056/NEJMoa2001282(2020).,YeXT,etal.EurRevMedPharmacolSci.2020;24(6):3390-339
• Posthocanalysissuggestingearlytreatmentmaybeefficacious
Chloroquine Mechanisms Against SARS-CoV-2
• BlocksviralinfectionbyincreasingendosomalpHrequiredforvirus-cellfusion• InterfereswithglycosylationofSARS-CoVcellularreceptors• Chloroquineinterfereswithentryandpost-entrystagesofSARS-CoV-2infectioninVeroE6cells
SlidecourtesyMichaelMelia,MD
WangMetal.CellResearch(2020)30:269–271;https://doi.org/10.1038/s41422-020-0282-0.VincentMJetal.VirolJ.2005Aug22;2:69.
Chloroquine Mechanisms Against SARS-CoV-2 • VeroE6cellsinfectedwithSARS-CoV-2atMOI0.05• EfficacyevaluatedbyquantificationofviralcopynumbersincellsupernatantbyRT-PCR,confirmedwithvisualizationofvirusnucleoproteinexpressionthroughimmunofluorescencemicroscopyat48hpost-infection• EC90=6.90μM(clinicallyachievable)
SlidecourtesyMichaelMelia,MDWangMetal.CellResearch(2020)30:269–271;https://doi.org/10.1038/s41422-020-0282-0.
CQ versus HCQ in vitro
• CytotoxicityinVeroE6cellsmeasured• HCQlesspotentthanCQatsomeMOI
LiuJetal.CellDiscovery(2020)6:16.https://doi.org/10.1038/s41421-020-0156-0
SlidecourtesyMichaelMelia,MD
Hydroxychloroquine Clinical Data (Preprint) • Randomized,parallel-grouptrial• Inclusioncriteria:
• Age≥18y• SARS-CoV-2RT-PCRpositive• ChestCTwithpneumonia• SaO2:SpO2>93%orPaO2:FiO2>300mmHg
• Exclusioncriteria:• Severe,criticalillness
• Retinaldisease• Heartblock• Severeliverdisease,includingAST>2xULN• Pregnantorbreastfeeding• eGFR≤30orRRT
SlidecourtesyMichaelMelia,MDChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758
Hydroxychloroquine Clinical Data (Preprint) • 62patients
• 47%men• Meanage44.7y±15.3
• Allreceivedstandardtherapy• Oxygen• Antiviralandantibacterialagents• Immunoglobulin±corticosteroids
• RandomizationtoHCQ200mgBIDx5dvsstandardtreatment
• Outcomes• Timetoclinicalrecovery=afebrileandcoughrelief≥72h• ChestCTd0vsd6• InitiallyplannedPCRandT-cellrecoverydatanotreported
• HCQ:9nofever,9nocough• Control:14nofever,16nocough
ChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758
SlidecourtesyMichaelMelia,MD
Hydroxychloroquine Clinical Data (Preprint) • FeverdurationshorterwithHCQ(2.2±0.4dvs3.2±1.3d)• CoughdurationshorterwithHCQ(2.0±0.2dvs3.1±1.5d)• MorepatientshadradiographicimprovementwithHCQ[25/31(81%)vs17/31(55%),p=0.05]• All4patientswhoprogressedtosevereillnesswereincontrolgroup• 2patientswithmildadversereactionsinHCQgroup(rash,HA)
ChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758
SlidecourtesyMichaelMelia,MD
Hydroxychloroquine Clinical Data
• 30patientsatasinglecenterinChina• RandomizedtoHCQ400mgdailyx5d+conventionaltreatmentorconventionaltreatmentonly• Bothgroupsreceivedinterferon• Mostreceivedumifenovirorlopinavir/ritonavir
• Primaryendpoint:negativeNPswab7dafterrandomization
• Nodifferenceinprimaryendpointbetweengroups• 13/15(87%)casesnegativeinHCQgroup,14/15(93%)incontrolgroup
• NodifferenceintimefromhospitalizationtonegativeNPswab,feverresolution,radiographicfindings,diarrheaorabnormalliverenzymes
ChenJ.JZhejiangUniversity.2020:[Epubaheadofprint].https://doi.org/10.3785/j.issn.1008-9292.2020.03.03.https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx.Accessed13April2020.
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• Open-label,non-randomizedtrialinFrance• Patientsaged≥12ywithNPSARS-CoV-2carriageonadmission
• Excluded:retinopathy,G6PDdeficiency,QTintervalprolonged,pregnancy• HCQ200mgTIDx10d±azithromycin500mgx1then250mgQDx4d
• Controls:untreatedpatientsfromanothercenter,patientsrefusedprotocol
• NPswabVLmeasureddaily• Endpoint:presenceofvirusatday6post-inclusion
GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• 36*patients• Meanage45.1±22y• 42%(15/36)men• 4.0±2.6dbetweensymptomonset&inclusion
• Clinicalcharacteristics• 8patientswithLRTIsymptoms(allhadevidenceofpneumoniabyCTscan)• 22patientswithURTIsymptoms(rhinitis,pharyngitis,fever,myalgia)• 6asymptomaticpatients
GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• Atday6post-inclusion:• 70%HCQ-treatedpatients(vs12.5%controls)testedNPRT-PCRnegative• 100%HCQ+azithromycin-treatedpatients(vs57%patientstreatedwithHCQmonotherapy)testedNPRT-PCRnegative
GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• OnepatienttreatedwithHCQ+azithromycintestedRT-PCRnegativeatday6andthenpositiveatday8• PatientstreatedwithHCQ+azithromycinhadlowerviralRNAloadsattreatmentinitiationthanHCQandcontrolgroups• SitesotherthantheprimarysitedidnotperformdailyPCRtesting
• 38%ofdataforcontrolgroupimputed(vs5%fortreatmentgroup)
• 6treatedpatientsomittedfromanalysisowingtoICUtransfer(3),death(1),hospitaldischarge(1),nausea(1)
GautretPandLagierJCetal.IntJAntimicrobAgents(2020),doi:https://doi.org/10.1016/j.ijantimicag.2020.105949.KimAHJ,SparksJAetal.AnnInternMed.Doi:10.7326/M20-1223
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• 11consecutivepatients• 7men,4women• Meanage59y(range20-77)• 8withsignificantcomorbidities
• HCQ600mgdailyx10d+azithro500mgx1then250mgQDx4d• Attreatmentinitiation,10/11hadfeverandwerereceivingoxygen• Within5d,onepatientdied,twotransferredtoICU• Onecoursediscontinuedafter4d(QT405→460-470)• NPRT-PCRpositivein8/10patientsat5-6daftertreatmentinitiation
MolinaJMetal.MedecineetMaladiesInfectieuses(2020),doi:https://doi.org/10.1016/j.medmal.2020.03.006
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• Caseseriesof80patientsatoneinstitution• AllpatientstreatedwithHCQ200mgTID+azithromycin500mgx1then250mgQDfor≥3d&followedfor≥6dincluded
• Excluded:QTc>500ms,ECGsuggestingchannelopathy
• HCQ200mgTIDx10d±azithromycin500mgx1then250mgQDx4d• CeftriaxoneaddedforpneumoniaandNEWSscore≥5
• NPswabVLmeasured~dailybyRT-PCR• Primaryendpoints:
• Clinicaloutcome,includingO2therapyorICUtransferafter≥3dtreatment• ContagiousnessasassessedbyPCRandculture• Lengthofinpatientstay
GautretPandLagierJCetal.https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• 80patients• Medianage52.5y(IQR42-62)• 52.5%(42/80)men• 57.5%atleastonechroniccondition• 4.9±3.6dbetweensymptomonset&treatmentinitiation
• Clinicalcharacteristics• 54%LRTIsymptoms• 41%URTIsymptoms• 5%asymptomatic• 15%hadfever• 92%lowNEWSscore(0-4)
GautretPandLagierJCetal.https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
SlidecourtesyMichaelMelia,MD
HCQ + Azithromycin
• 15%(12/80)receivedO2
• 81%(65/80)discharged• 17%(14/80)stillhospitalized• 4%(3/80)transferredtoICU• 1%(1/80)died• Meantimefrominitiationtohospitaldischarge4.1d• MeanLOS4.6d
GautretPandLagierJCetal.https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
SlidecourtesyMichaelMelia,MD
HCQ Clinical Trials: Examples
Name/Sponsor PertinentCharacteristics Estimatedcompletion
ACTG5396 Hospitalized Pending
ACTG5395 Outpatients Pending
MultipleProphylaxistrials HCWsorhouseholdcontacts Ongoing
SOLIDARITY/WHO 8.Hospitalized March2020-2022
DISCOVERY/INSERM 9.Hospitalized March2020-2023
On the Horizon Antivirals ImmuneModulators Other
Baloxavir Anakinra ACEI/ARB
Chloroquine/Hydroxychloroquine ConvalescentPlasma AscorbicAcid
DAS-181 Corticosteroids Azithromycin
Favipiravir IVIG Epoprostenol
Interferon Lenzilumab Indomethacin
Lopinavir/Ritonavir Ruxolitinib Ivermectin
Neuraminidaseinhibitors Sarilumab Niclosamide
Remdesivir Sirolimus Nitazoxanide
Ribavarin Tocilizumab Statins
Umifenovir Acalabrutinib
“Antiviral” Key Points
• RemdesivirhasbiologicalplausibilityandinvitrodatatosupportitscandidacyasaSARS-CoV-2therapeuticagent• Clinicaltrialdataforthcoming
• Lopinavir/ritonavirhasminimalsupportiveinvitrodatainSARS-CoV-2• CurrentclinicaldatadoesnotsupportitscandidacyasaSARS-CoV-2therapeuticagent
• Clinicaltrialdataforthcoming• Inpatientswithnon-severedisease,andaspartofmulti-componenttherapy,HCQmay:• Beassociatedwithshorterdurationsoffeverandcough• Beassociatedwithradiographicimprovement
• InadequatedatatocommentonimpactofHCQonviralRNAshedding
COVID-19 Cytokine Release Syndrome
• SimilartoCRSseeninCART-TTherapy• DrivenbyIL-6• AntiIL-6blockade:Tocilizumabutilized
• LikeinCAR-Ttherapy,appearstobecharacterizedby• Fever• Bloodpressureabnormalities• Progressiverespiratorydecline• Elevationofcertaininflammatorylaboratories
• ARDS≠CytokineReleaseSyndrome
MehtaP,etal.Lancet.2020;395(10229):1033-1034.
Observational Cohorts: Published
• Retrospectiveobservationalstudyof15patientsadmittedtoahospitalinChina• Classifiedintomoderatelyill(13%),seriouslyill(40%),criticallyill(47%)• Medianage73[IQR62-80]
• Heterogeneousdosing,timing• Halfreceivedmethylprednisolone
LuoP,etal.JMedVirol.doi:10.1002/jmv.25801(2020).
Observational Cohorts: Published
• 3patientsdied(20%)• Wheninclinicalcoursedidpatientsreceivetocilizumab?• WeretheyARDSordevelopingsignsofCRS?
LuoP,etal.JMedVirol.doi:10.1002/jmv.25801(2020).
Observational Cohorts: Preprint
• Retrospectiveobservationalstudyof21patientswithprovenCOVID-19admittedto2hospitalsinChina• Definedas
• Severe:RR≥30breaths/min,SpO2≤93%onambientair,PaO2/FiO2≤300mmHg
• Critical:Mechanicalventilation,shock,organfailurerequiringICUadmission
• Patientsreceivedstandardofcare+tocilizumab• Standardofcare=lopinavir/ritonavir,methylprednisolone,oxygen
XuX,etal.http://www.chinaxiv.org/abs/202003.00026(Accessed4/19/2020).
Observational Cohorts: Preprint
• 19%dischargedattimeofpapersubmission• BasedonthisdataNationalHealthCommissionofChinaincludedtocilizumabinCOVID-19therapyrecommendations• Wheninclinicalcoursedidpatientsreceivetocilizumab?• WeretheyARDSordevelopingsignsofCRS?
XuX,etal.http://www.chinaxiv.org/abs/202003.00026(Accessed4/19/2020).
Observational Cohorts: Preprint
• 21patientswithCOVID-19andARDSinItaly• Usingnoninvasiveventilation• PartofSiltuximabcompassionateuseprogram• Medianage64years[IQR48-75];18(85.7%)men• MedianIL-6139.5pg/mL,CRP23.4mg/dL• Comorbidities
• Hypertension:9(42.3%)• Diabetes5:(23.8%)• Cardiovasculardisease4(19.1%)
• Median3dayshospitalizationpriortosiltuximab
GrittiG,etal.https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf.Accessed4/20/20
Observational Cohorts: Preprint
GrittiG,etal.https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v2.full.pdf.Accessed4/20/20
Themes Of Current Clinical Data
• Outcomerelatedtotocilizumabornaturalhistory• Heterogeneityinpatients• Variabilityinclinicalcourse• Variabilityinadministration
• Dosing• Timingofadministration
• Concomitantuseofotheragents/anti-inflammatories• Heterogeneousoutcomes
Anti IL-6 Key Points
• SomepatientswithCOVID-19maydevelopasyndromesimilartothecytokinereleasesyndromeseeninCAR-Ttherapy• Characterizedbyspecificclinicalfindingsandinflammatorylaboratories
• Thereisapaucityofreliablepublisheddata• Clinicaltrialdataforthcoming• Anecdote:earlyadministrationappearsmoreeffectivethanlateinthecourseofillness
Convalescent Plasma
• IntheUS,IND• Clinicaltrials,expandedaccess,emergencyindividualuse
• Currentdata:Casereports/series• Limitations:Plasma• StudylaunchingatJHH
ConvalescentPlasma
ChenZ.medRxivpreprintdoi:https://doi.org/10.1101/2020.03.22.20040758
Objectives
• ReviewbiologicalplausibilityofRemdesivirforSARS-CoV-2treatment• ReviewclinicaldataonRemdesivir• ReviewbiologicalplausibilityofHydroxychloroquineforSARS-CoV-2treatment• ReviewclinicaldataonHydroxychloroquine• DiscusscytokinereleasesyndromeinCOVID-19• DiscussuseofantiIL-6blockadeformanagementofCRS• StateongoingclinicaltrialsforRemdesivir,hydroxychloroquine,IL-6blockade