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:

PleaseemailCatherine.Freeland@hepb.org ifyouwouldliketosubmitacaseforpresentation.

CMECredit:

Post-Test:https://www.surveymonkey.com/r/6V2XHVJ