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HepatitisBProjectECHOMarch25th,202112pmEasternTimeReoccurringevery4th Thursday
AgendaIntroductions(10minutes)
ProjectECHODefinedandSessionFormat (2minutes)CatherineFreeland
DidacticPresentation:HBcAb (15minutes)RobertGish,MD,
CasePresentation (5-10minutes)
CaseFeedbackandRecommendations(15minutes)
IntroductionsName,Affiliation
TheECHOModel
Anti-HBc:StateoftheArtWhatistheCOREoftheIssues?
RobertGishMD,FAASLD,AGAF,FASTRobertGGishConsultantsLLC– Principal
ProfessorofMedicine– LomaLindaUniversityHepatitisBFoundation- MedicalDirector
AdjunctProfessorofMedicine:UniversityofNevadaLasVegasUniversityofNevadaReno
UCSDSkaggsSchoolofPharmacyandPharmaceuticalSciences
Epidemiology- Worldwide
• 2BillionPeoplehaveHBVdiseasedefinedasanti-HBc(+)andwhohaveHBVDNA/cccDNA intheirliverhaveserologicevidenceofexposure,and“past”orpresentHBVinfection,Definedbyanti-HBc+
• 292MillionHBsAg(+)CarriersWWandupto2.4MintheUSarechronicallyinfectedwithHBV
• 1MillionPeopleormoreWWdieeachyear fromHBV-relatedChronicLiverDiseases
HBVTestsPartI:Allpatientsneedthis“triplepanel”whenevaluatingforHBV
• +HBsAg = infection (Test all patients for HDV)
• +Anti-HBc = exposure = cccDNA = persistence– Eval for Occult HBV if HBsAg (-) and anti-HBs(-)– Educate about HBV reactivation risk with HCV DAA and
immunomodulating agents/treatments– Advise: No HBV vaccine boosting
• +Anti-HBs = immunity, only if anti-HBc is negative
• Note:– HBV is incurable– There is no “natural immunity” to HBV
Whatarethebasicconcepts?
• HBVis aDNAviruslikeEBVCMVHSVVSZ andisincurable,allpatientshavearemnantofHBVDNAintheirliverintheformofcccDNA
• HBVhasnonaturalimmunity• Anti-HBcisthetestforHBVexposure= HBVinfection=remnant
HBVintheliverduetothelife-longpersistenceofcccDNA• Anti-HBc+hasafalse(+)rateat0.2%eveninlowriskorverylow
riskpatients• Anti-HBc(+)indicatesagradientofriskforreactivationbasedon
thetypeofimmunesuppressionorHCVDAAtreatment• Anti-HBs+andtitersarenotprotectiveagainstreactivation
• Hightitersofanti-HBshasaslightlylowerriskofreactivation,buttheriskremainssubstantial,adecliningtiterindicatesahigherriskofreactivation,thereisnodatathat“boosting”anti-HBswithaHBVvaccinedoseinapatientwithanti-HBchasanyvalue
• AnyHBVVaccinedoseforpatientswithanti-HBc(+)hasnoroleinthepeerreviewliterature,thereisnoroleforboostinganti-HBs
GlobalPrevalenceofAnti-HBcPositivityamongLiverDonors
(PublishedData)
5
12
79
5457
0
10
20
30
40
50
60
Prevalen
ce,%
USA Spain
•Multiple Studies•CholongitasE,etal.JHepatol 2010;52:272-279.
JapanFrance China Taiwan
Isdevelopmentofanti-HBs“protective”?Inpatientswhoareanti-HBc(only){+}?
• Historically;patientswhoareanti-HBsandanti-HBc(+)wereconsideredtobe“naturally”immune
• Thisterminologyisanoxymoron
• HBVisachronicdiseaseandonceinfectedpatientsretainHBVinnucleustheformofcccDNAinliverorportionsofthevirusasintegratedDNA.
• HBVissimilartootherDNAviruses:CMV,EBV,herpesfamily:thereisnocureforanyoftheseinfections
TheAnswerIs:
• Anti-HBs(+)inthesettingofAnti-HBc(+)andHBsAg(-)
• Anti-HBsprovides:Someprotectionfromreactivationif(+)afternaturalinfection
• Highernaturaltiters:moreprotectionfromreactivation
• Decreasingtiters:higherriskofreactivation
• Thisisnorelevantdatatosupportvaccine“boosting”
PerrilloGastro2015
Summary:ifanti-HBc+:useprophylaxisaccordingtoguidancedocumentandrisk
Rituximab-AssociatedHBVReactivationinLymphoproliferativeDisorders
Meta-analysisandreviewofFDAsafetyprofiles
Casereports(n=27)Caseseriesreports(n=156)
OnsetpostlastrituximabdoseMedian:3months(range:0-12months)>6months:29%
Reactivationinanti-HBcpositivepatientsreceivingrituximabversusnorituximab
Oddsratio:5.73(P=0.0009)
Evens AM, et al. Ann Oncol. 2011;22:1170-1180.
Hui(n=233)
Tsutsumi(n=47)
Targhetta(n=319)
Yeo(n=50)
Fukushima(n=48)
Overall(n=697)
HBV Reactivation Risk:Rituximab-Treated Lymphoma Patients
0.32 1.0 3.16 31.62Odds Ratio
12.44
5.24
3.38
9.39
1.60
5.64(2.18-14.54)
ChenGDet.al,TransplantInfectious Disease8MAR2013DOI: 10.1111/tid.12065
Isanti-HBsprotectiveagainstreactivation:?Outcomesandriskfactorsfor hepatitisBvirus(HBV)
reactivationafterkidneytransplantationinoccultHBVcarriers
AntibodytestingtoHBc:whatarethecurrentdetails?
Summaryoftheimprovementsofanti-HBctestperformance
1) UsearecombinantHBcAg thathasabroadlyprevalentserotypesuchasayw
2) UsewellcharacterizedserumspecimensofpatientswithknownpastHBVinfection
3) ChooseappropriateS/COlevels
4) Considerconfirmingwithanti-HBe whendevelopingnewantibodytestingtoprovespecificity
5) WHOnowhasthefirstinternationalstandardforanti-HBcwhichisderivedfromthePEI(PaulErlich Institute)standard
Whendoesanti-HBcappearafteracuteinfection?Acute hepatitis B virus infection with delayed appearance of hepatitis B core antibody in an immunocompromised
patient: a case reportAbstract
BackgroundDespite the introduction of universal hepatitis B immunization programs worldwide, outbreaks of acute infection still occur in unimmunized individuals. A timely diagnosis of hepatitis B is necessary to ensure adequate clinical care and public health interventions that will reduce transmission. Yet, interpretation of hepatitisB serological markers can be complex. We present a case of hepatitis B with atypical markers, including delayed appearance of hepatitis B core
antibody.
Case presentationA 62-year-old white woman was identified as a sexual contact of a male individual with acute hepatitis B virus infection. She had a history of recurrent low-grade non-Hodgkin lymphoma and had recently received immunosuppressive therapy. At baseline she had a negative serology and received three double doses (40 μg) of Engerix-B vaccine (hepatitis B vaccine) with a 0-month, 1-month, and 6-month schedule. One month following the last dose, hepatitis B surface antigen was positive in the absence of hepatitis B core antibody. The only sign of infection was a slight elevation of alanine aminotransferase enzymes a few months after first sexual contacts with the male individual. Hepatitis B virus infection was later confirmed despite the absence of hepatitis B core antibody. The development of hepatitis B core antibody was finally noted more than 6 months after the first positive hepatitis B surface antigen and more than 12 months after elevation of alanine aminotransferase enzymes. Immunosuppression including rituximab treatment was the most likely explanation for this serological profile. On her last medical assessment, she had not developed HBeAg seroconversion despite lower hepatitis B virus deoxyribonucleic acid levels with tenofovir treatment.
Conclusions
When confronted with positive hepatitis B surface antigen in the absence of hepatitis B core antibody, consideration should be given to the possibility of both acute and persistent infection particularly in the setting of immunosuppression so that appropriate clinical management and public health interventions can take place. Given the increasing use of biologicals such as anti-tumor necrosis factor therapies either alone or with other immunosuppressive agents, this phenomenon may be encountered more frequently.J Med Case Rep. 2017; 11: 111.Published online 2017 Apr 17. doi: 10.1186/s13256-017-1264-9PMCID: PMC5393022
Whatisrateofanti-HBs(+)ifanti-HBc(+)?
• Anti-HBs(+)in93.7%inblooddonorswhoareanti-HBc(+)
• Inverse:Anti-HBc(+)“only”is6%ofpatientstested
HBVDNAinDonors withIsolated Anti-HBc Ab
1.6logIU/ml
3.6logIU/ml
20%
40%
60%
80%
100%
0%
2/53(3.8%)2/21(9.5%)
Brain-deadorgandonors(n=199)
Livingorgandonors(n=13)
TissueDonors(n=165)
CordbloodDonors(n=56)
StemcellDonors(n=75)
CorneaDonors(n=118)
AlsoseeTransfusion2003;43:696-704.
Efficacy of serologic marker screening in identifying hepatitis B virus infection in organ, tissue, and cell donors.Challine D, Chevaliez S, Pawlotsky JM.Gastroenterology. 2008 Oct;135(4):1185-91. doi: 10.1053/j.gastro.2008.07.011. Epub2008 Jul 17.
SerumHBsAg,anti-HBc,anti-HBs
HBsAg-positive/anti-HBc-positive
AcuteorchronicHBVinfection
Consideranti-HBcIgMifacute
elevationinlivertests
Anti-HBshasnoclinicutilityinthis
setting
HBsAg-negative/anti-HBc-positive
Falsepositivetest:rare
<2/1000
ChronicHBVinfectionwithantigenicallymodified's'mutantvirus
OccultHBVinfection
HBVDNA(+)
ComplexformationofHBsAgandanti-
HBs
LatephaseofHBVinfection,immune
control
AFocusonOBI
2.4logIU/ml
20%
40%
60%
80%
100%
0%
3/62(4.8%)
HBVDNAinDonors with BothAnti-HBc andAnti-HBs Ab
Brain-deadorgandonors(n=199)
Livingorgandonors(n=13)
TissueDonors(n=165)
CordbloodDonors(n=56)
StemcellDonors(n=75)
CorneaDonors(n=118)
CHALLINEetal
HBVDNAin“anti-HBc-only”units
Sample dates 1991-95 2001 2002-03
No. tested 395 3,000 3,956
No. DNA-pos 4 19 14
Rate: Calc’ted Direct Direct
per HBc-pos 0.24% 0.63% 0.35%
per tx unit 1:49,000 1:37,000 1:54,000
Viral Load (copies/mL)
all < 100 68% < 100 93% MP-NAT (-)
Parameter REDS ARC Roche
Reactive Non-Reactive
Total
Positive 19* 0 19
Negative **2335
(79%)638
(21%)2973
Total 2354 638 2992
*MeanS/CO=0.14(range0.02-0.49);S/CO< 1.00=Reactive**7SamplesPCRNegative;PRISMHBcore QNS
PRISManti-HBc
NGIH
BVUltraQ
ual1000
Profile1 Profile2 Profile3 Profile4 Profile51.HBsAg Negative Negative Positive Negative Negative2.Anti-HBc Negative Negative Positive Positive Positive3.AntiHBs Negative Positive Negative Positive NegativeSignificance 1.Nochronic
infection;notahepatitisBcarrier.
1.Nochronicinfection;notahepatitisBcarrier.
1.Hasacuteorflare(ifHBc IgM+)or99%chronichepatitisBinfection.
1.NohepBinfectioninthebloodifHBVDNAnegative
1.SubclinicalinfectionatthemomentifHBVDNA+OBI
2.NeverbeeninfectedwithhepatitisBvirus.
2.NotinfectedwithhepBvirus.
2.IsinfectedwithhepBvirus.HascccDNAintheliver
2.HasbeeninfectedwithhepBvirus.HascccDNAintheliver
2.HasbeeninfectedwithhepBvirus.HascccDNAintheliver
3.Noimmunity(noprotection)againsthepB.
3.Hasimmunityduetovaccination.
3.NoimmunityorprotectionagainsthepB.
3.HasclearedthebloodofHBVinfection(whencombinedwithnegativeHBsAg)Andhasimmunecontrol
3.OBI:subclinicalinfectionHBVDNA+andhasriskofreactivation.
Action -- -- SeePrimarycareproviderforfurthertests.HBVDNAquant.
Watchforreactivationifbecomesimmunesuppressed
WatchforrisksofreactivationifpatientbecomeimmunesuppressedNovaccinationboosting
Providevaccination
Novaccinationneeded
Novaccinationneeded
Novaccinationneeded Novaccinationneeded
InterpretationHBVserologictestresultsforHBVinfectionandFurtherActions
SummaryandConclusions
Preliminarydataindicatefeasibilityofanti-HBcreentryalgorithm
All19HBVDNA-positivesamplesdetectedasreactivebyAbbottPRISManti-HBcore ChLIAAll19stronglyanti-HBcreactive
MeanS/CO=0.14(range0.02-0.49)
Yieldofreentrydependentonpriorassay25%forOrtho=>Ortho(1X=>2X)21%forOrtho=>PRISM(pilotstudy)40%forOrtho=>PRISM(Hema-Quebec)??forCorzyme (priorAbbott)=>PRISM
FutureConsiderations
• RoleofNucleicAcidTestingandsubsequentorganallocation
• DeterminenaturalhistoryofdenovoHBVinfection
• Harmonizeposttransplantprophylaxisstrategyuseornon-useofHBIgNucleos(t)ideanaloguse-finitedurationVsindefiniteuseHBVvaccinationstrategies
It’scriticalinthissettingthatHBVnucleicacidtestinguseahighlysensitiveassaycapableofdetecting<10copies/ml.
THANKYOU
RobertGishMD,FAASLD,AGAF,FASTRobertGGishConsultantsLLC– Principal
ProfessorofMedicine– LomaLindaUniversityHepatitisBFoundation- MedicalDirector
AdjunctProfessorofMedicine:UniversityofNevadaLasVegasUniversityofNevadaReno
UCSDSkaggsSchoolofPharmacyandPharmaceuticalSciences
HepatitisBCasePresentationKatieHuynh,PA-C,MS,AAHIVM-S
NextSession:Feb.25th @12PMET
Callforcases:
[email protected] ifyouwouldliketosubmitacaseforpresentation.
CMECredit:
Post-Test:https://www.surveymonkey.com/r/6V2XHVJ