Hepatitis B and cancer: A practical guide for the oncologist

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ContentslistsavailableatScienceDirect

Critical

Reviews

in

Oncology/Hematology

j ou rn a l h o m e pa g e :w w w . e l s e v i e r . c o m / l o c a t e / c r i t r e v o n c

Hepatitis

B

and

cancer:

A

practical

guide

for

the

oncologist

Claudia

Bozza

a,b,∗

_,

_Marika

_Cinausero

a,b

_,

_Donatella

_Iacono

a,b

_,

_Fabio

_Puglisi

a,b

a_Department_of_Oncology,_University_Hospital_of_Udine,_Udine,_Italy

b_Department_of_Medical_and_Biological_Sciences,_University_of_Udine,_Udine,_Italy Contents

1. HepatitisBandcancer:numbersandburdenofdisease...137

2. HepatitisBinfection:severalwaystowearamask ... 138

3. Howmanytypesofhepatitisarethere?Navigatingaseaofdeﬁnitions...138

4. HBVserology:unravellingthepuzzle...139

5. HBVreactivationduringchemotherapy:cloudsonthehorizon ... 140

6. ProphylaxisandtreatmentofHBVreactivation:thestateoftheart...140

7. OccultHBVinfection:thehiddenenemy...141

8. HBV:toscreenornotscreen...141

9. WhataboutHCV?...143

10. Conclusions:takestockofthesituation!...144

Conﬂictofinterest...144 References...145 Biographies...146

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Articlehistory: Received23July2015

Receivedinrevisedform7October2015 Accepted28October2015 Keywords: Hepatitis Cancer Chemotherapy Immunosuppression Reactivation HBV

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HepatitisBvirus(HBV)infectionisaworldwidediseaseassociatedwithsignificantmorbidityand mor-talityandafteracuteinfection,HBVinfectioncanpersistinabout1-2%ofimmunocompetenthosts. Chemotherapy-inducedimmunosuppressioncanleadtoHBVreactivationandmaycause discontinua-tionofanticancertreatment,fulminanthepatitiswithliverfailureanddeath.Duringimmunosuppressive treatmentssuchaschemotherapy,reactivationofHBVinfectionisalife-threateningcomplicationthat canoccurinHBVactiveorinactivecarriersbutalsoinpatientswithOBI.OccultHBVinfection(OBI) isdefinedasthepresenceofdetectableverylowlevelsofHBVDNAinHBsAg-negativepatients.Many literaturedatashowedabenefitfromprophylacticantiviraltreatmentincancerpatientsatriskforHBV reactivation,howeverthereisnoevidenceindeterminingthebenefitofroutinescreeningforchronic HBVinfectioninallpatientsundergoingcytotoxicandimmunosuppressivechemotherapy.Major guide-linesrecommendHBVscreeninginHBV-infectionhighriskpatientsoriftheimmunosuppressioncaused bythetreatmentisexpectedtobehigh.

1. HepatitisBandcancer:numbersandburdenofdisease HepatitisBvirus(HBV)infectionisaworldwideproblem associ-atedwithsigniﬁcantmorbidityandmortality.Ithasbeenestimated thattwobillionpeoplehavehadhepatitisBvirusexposureand near400millionhaveexperiencedchronicinfection(Sagnellietal., 2012).Afteracutehepatitis,HBVinfectionpersistsinabout1–2%

∗ Correspondingauthorat:DepartmentofOncology,UniversityHospitalofUdine, PiazzaleS.M.Misericordia1,Udine,Italy.

E-mailaddress:bozza.claudia@gmail.com(C.Bozza).

ofimmunocompetenthostsandinhigherpercentageof immuno-suppressedpatients(Lavanchy,2005).

Thechronicinfectionincreasestheriskofdevelopingcirrhosis andhepatocellularcarcinomaupto40%(McQuillanetal.,1999;De Jonghetal.,1992).Moreover,HBV-carrierpatientscouldpresent, duringtheircourseoflife,othermalignanciesunrelatedtohepatitis virusesforwhichchemotherapytreatmentisindicated. Further-more,chemotherapy-inducedimmunosuppressioncanleadtoHBV reactivationandmaycausehepatitisandliverfailure, discontinu-ationofanticancertreatmentanddeath.

http://dx.doi.org/10.1016/j.critrevonc.2015.10.017

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mentcanresultsinlife-threateningeventsandinpooroutcome duetoearlydiscontinuationofchemotherapy.

Inclinicalpractice,theoncologistsdealwithalargenumberof patientsundergoinganticancertreatmentsandwiththe uncertain-tiesaboutscreeningandprophylaxisagainstHBV.

Theaimofthisreviewistoprovideapracticalandconciseguide forthemedicaloncologistaboutdiagnosis,deﬁnitions,screening andmanagementofHBVinfectionincancerpatients.

2. HepatitisBinfection:severalwaystowearamask

The pathogenesis and clinical manifestations of hepatitis B infectionareduetotheinteractionbetweenthevirusreplication andthehost’simmunesystemresponse,especiallylymphocyte lin-eage.Theimmunologicreactioncausesliverinjuryand,ifimpaired ortolerant,canresultinchronichepatitis(Jungetal.,1994;Chisari, 1997).FivestagescanbeidentiﬁedinthevirallifecycleofHBV (TorresandDavila,2012;Hoofnagle,2009).

• Theimmunetolerancestagerepresentstheincubationperiod. Thevirusreplicateswithoutadeepactivationofimmune sys-tem,oftenwithnormallevelsofserumalanineaminotransferase (ALT).

• Theimmuneactivestageisaninﬂammatoryreactionwith hep-atocytenecrosis.Inpatientswithacuteinfectionthedurationof thisstageisapproximatelyonemonthandisaccompaniedby avarietyofsymptoms.Inchronicinfectionsthisphasecanlast overtenyearsbeforeonsetofcirrhosis,immuneclearancephase takingplaceorhepatocellularcarcinomadevelopment.

• Theinactivechronicinfectionconsistsinlowornon-measurable viralreplicationandserumALTlevelswithinthenormalrange. Duringthisphasetheintegrationofviralgenomeintohepatocyte geneticcodecouldtakeplace.

• Chronicdiseasecanresult fromtheinactive chronicinfection phaseorfromimmuneactivestage.

• Recoveryisthediseasestageinwhichviruscannotbedetected inthebloodandantibodiestoviralantigensareproduced.

HBVinfectionisassociatedwithcharacteristicchangesinthe serum levels of hepatitis Bantigens and antibodies and these markersare useful todeﬁnedifferent clinicalstages of disease (Figs.1and2).

HepatitisBsurfaceantigen(HBsAg)istheserologichallmarkof HBVinfection;itappearsinserumduringtheincubationperiod, after1–10weekstheacuteexposuretoHBVandpriortotheonset ofhepatiticsymptomsorelevationofserumALT.Inpatientswho recoveredfromtheinfection,HBsAgisundetectableafteraperiod offourtosixmonths.Ontheotherhand,thepersistenceofthe markerformorethansixmonthsrevealsachronicinfection.

ThedisappearanceofHBsAgisfollowedbytheappearanceof hepatitisBsurfaceantibodies(anti-HBs).Inmostpatients,anti-HBs conferlong-termimmunityandoftenalifelongone.Insomecases, thereisawindowperiodofseveralweeksduringwhichneither HBsAgnoranti-HBscanbedetectedintheserum.On theother hand,in24%ofHBsAgpositivepatients,HBsAgandanti-HBscan coexistbuttheseantibodiesareunabletoneutralizethecirculating viruses(Tsangetal.,1986).

HepatitisBcoreantigen(HBcAg)isnotdetectableintheserum becauseisanintracellularantigenofinfectedhepatocytes.

recoveryfromacuteinfectionforaperioduptotwoyearsandthey increaseduringexacerbationsof chronichepatitisB(Maruyama etal.,1994).IgGanti-HBcpersistinassociationwithanti-HBsin patientswhorecoveredfromacutehepatitisBandtheyalsopersist alongwithHBsAginthosewhodevelopchronicHBVinfection.

HepatitisBeantigen(HBeAg)isasecretoryproteingenerally consideredamarkerofHBVreplicationandinfectivity.The pres-enceofHBeAgisusuallyassociatedwithhighlevelsofHBVDNAin theserumandhigherratesofHBVtransmission.Inpatientswith acuteinfectiontheseroconversion fromHBeAgtohepatitis Be antibodies(anti-HBe)occursearly,priortoHBsAgtoanti-HBs sero-conversion;however,HBeAgseroconversionmaybepostponedfor manyyearsinpatientswithchronicHBVinfection,often reveal-ingactiveliverdiseaseandhighserumlevelsofHBVDNA.The seroconversionfromHBeAgtoanti-HBeisusuallyrelatedwitha decreaseinserumHBVDNAandoftenwitharemissionofliver disease(Hoofnagleetal.,1981;Realdietal.,1980).

Whenpatientsrecoverfromacutehepatitis,serumlevelsofHBV DNAdisappearwhendeterminedbyhybridizationorbDNAassays, buttheycouldremaindetectableiftestedbyPCRassays(Carman etal.,1989).ThisfactsuggeststhatHBV,evenifapatientrecovers frominfection,maypersistinthehostcontrolledbytheimmune system.HBVDNAisamajorinstrumentfortheassessmentofviral replicationthatisinturntheprinciplecriteriainﬂuencingthe clin-icaldecisionaboutthetimingofantiviraltherapy andresponse evaluationtotreatment.

3. Howmanytypesofhepatitisarethere?Navigatingasea ofdeﬁnitions

ChronichepatitisB:Chronicnecroinﬂammatorydiseaseofthe liver caused by HBVpersistent infection.Serological markerof chronicinfectionisHBsAgpersistingmorethansixmonths; more-over,itcanbedividedinHBeAg-positiveandnegativeforms.

ActiveHBsAgcarrier:ApatientpresentingHBsAginserumis con-sideredHBVactivecarrierinthepresenceofHBeAgoranti-HBeand HBVDNA>20000UI/mL.

Inactive HBsAg carrier:A patientpresenting HBsAg in serum isconsideredHBVinactivecarriersifHBeAgis absent,anti-HBe presentandHBVDNA<20000UI/mL.

OccultHBVcarrier:HBsAg-negativepatientpresentingHBVDNA intheliver,withundetectableorverylow(<200UI/mL)HBVDNA intheserum.

ResolvedhepatitisB:PreviousHBVinfectionwithoutvirological, biochemical,orhistologicalevidenceofvirusinfection.

Windowperiod:TimebetweenthedisappearanceofHBsAgand the appearanceof anti-HBs.It takes place in several weeks or monthsandtheserologicaldiagnosiscanbemadebythedetection ofanti-HBcIgM.

AcuteexacerbationorﬂareofhepatitisB:Anabruptincreasein serumaminotransferaselevelswithorwithoutsymptomsof hep-atitisinapatientwithunderlyingchronicliverdisease.

ReactivationofhepatitisB:Reappearanceofnecroinﬂammatory diseaseoftheliverin aninactive HBsAgcarrier orin apatient witharesolvedhepatitisB.Inoccultinfection,theconversionof serumHBVDNAtestfromnegativetopositiveorthereappearance ofHBsAgaresignsofreactivation.

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Fig.1. AntigensandantibodiesproﬁleinacuteHBVinfection.

Fig.2.AntigensandantibodiesproﬁleinchronicHBVinfection.

HBeAgseroconversion:DisappearanceofHBeAgserumlevelsand appearanceofanti-HBe.

4. HBVserology:unravellingthepuzzle

SerologictestsforHBVantigensandantibodiesareusefulin conﬁrmingthediagnosisofHBVinfection,inselectingpatientsfor antiviraltreatmentandintheevaluationoftheresponseto treat-ment.Thefollowingtableshowstheinterpretationofserological testsforHBV(Table1).

Thediagnosisofacutehepatitisischaracterizedbytheserum detectionofHBsAgandanti-HBcIgM;intheinitialphaseof infec-tion, HBeAg and HBV DNA are alsopresent. Recovery phase is accompaniedbythedisappearanceofHBVDNA,theseroconversion fromHBeAgtoanti-HBeandsubsequentlyfromHBsAgtoanti-HBs. WhenHBsAg-positive acute hepatitis is suspected clinicians havetoconsiderpotentialdifferentialdiagnosissuchasacute hep-atitisB,exacerbationsofchronichepatitisB,reactivationofoccult hepatitisB, superinfectionofaHBVcarrierwithotherhepatitis viruses(Chu etal.,1989)andacuteexotoxichepatitisin aHBV carrier.

PreviousHBVinfectionischaracterizedbythepresenceof anti-HBs and antiHBcIgG. Acquiredimmunity dueto vaccinationis indicatedbythepresenceoftheonlyanti-HBs.

ThediagnosisofchronicHBVinfectionisbaseduponthe persis-tenceofHBsAgformorethansixmonths.Theinactivecarrierstate ischaracterizedbynormalALTlevels,absenceofHBeAg,presence

ofanti-HBe,andHBVDNAlevels<2000UI/mL.Activecarrierstate isdeterminedbyhighviralload(>20000UI/mL),whereasHBeAg couldbepresentorabsentwithanti-HBepositivity(Marcellinetal., 1990).

Occult HBV infection (OBI) is deﬁned as the presence of detectableverylowlevelsofHBVDNAinHBsAg-negativepatients. OBImaybeobservedinthewindowperiodduringacuteHBV infec-tion,intheabsenceofHBsAgandanti-HBs(isolatedanti-HBc),or inothersconditionslinkedtoimmunodepression,suchasHIVand HCV infectionorpharmacological immunosuppression(Sagnelli etal.,2014).

Theisolatedserologicalpresenceofanti-HBcintheabsenceof HBsAgandanti-HBshasbeenreportedinlessthan2%ofhealthy volunteersinlowHBVprevalenceareasandupto20%ofendemic areaspopulation(Loketal.,1988).Thisserologicalconditioncan occurinthreedifferentsituations:

• duringthewindowperiodofacutehepatitisB

• afterrecoveryfromacutehepatitisBwhenanti-HBshasfallento undetectablelevels

• aftermanyyearsofchronicHBVinfectionwhenHBsAgmaybe undetectablebecausethelossofHBsAg.Thisﬁndingoccursin 0.5%ofchronichepatitisBpatientsperyear.

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Acutehepatitis Positive Positive Negative Positive

Chronicpatient Positive Positive Negative Negative

Unclearinterpretation Negative Positive Negative –

testedtoruleoutwindowperiodofacuteinfection.Thedetection

ofanti-HBccouldbealsoafalsepositiveﬁnding.InthiscaseHBV

DNAdeterminationcouldbeconsideredinordertoﬁndchronic

infectionwithlowviralload.

5. HBVreactivationduringchemotherapy:cloudsonthe horizon

Duringimmunosuppressivetreatmentssuchaschemotherapy,

reactivationofHBVinfectionisalife-threateningcomplicationthat

canoccurinHBVactiveorinactivecarriersandinpatientswithOBI.

In fact, afterexposition to HBV thevirus can persistin the

bodyevenafterserologicalrecoveryfromacutehepatitis.

HBsAg-positive patientsreceiving chemotherapyhave a higher risk of

reactivationthatrangeapproximatelyfrom20to50%(Yeoetal.,

2004a;Hsuetal.,2014).

ReactivationofHBVinfectionwasﬁrstdescribedreferringto treatmentsofhematologicaldisease,suchasanti-CD20monoclonal antibodies(Setoetal.,2014),CHOPregimen(cyclophosphamide, doxorubicin,vincristineandprednisone)(Hsuetal.,2014)or ﬂu-darabine(Dominguezetal.,2015).

Nevertheless, an increasing number of cases have been described among patients treated withchemotherapy for solid tumorsgivingevidenceofHBVreactivationinthesecases.

Inparticular,patientsundergoingchemotherapyforbreast can-cerhavehigherrateofHBVreactivation(41–56%)thanothercancer patients(14–21%)(Liuetal.,2015;Yeoetal.,2003).Inaddition, morepatientswithreactivationundergopermanent discontinu-ationordelayoftreatment(76%)compared withthosewithout evidenceofreactivation(33%)(Yeoetal.,2003).

HBV reactivation is characterized by an important early enhancementofviralreplicationafterthestartofchemotherapy withspreadofHBVtohepatocytesandrisingserumHBVDNA lev-els.Thesemodiﬁcationscanoccuruptothreeweeksearlierthan laboratoryalterationsandcanbeaccompaniedbyserological reap-pearanceof HBeAgand HBsAg (seroreversion). Ina subsequent phase,afterchemotherapywithdrawal,theimmunological func-tionisrestoredleadingtocytotoxic-T-cellsmediateddestruction ofHBVinfectedhepatocytes.ThisresultsinincreasingALTlevels (hepaticﬂare)andmaycauseseveralclinicalmanifestationsthat canrangefromasymptomaticself-limitinghepatitistofulminant hepaticfailureorevendeath.Duringthisphase,HBVDNAlevels maydecrease.

ThereisnotadefinedconsensusaboutthedefinitionofHBV flare.Frequently,itisdescribedanincreaseinserumALThigher than5timestheupperlimitofnormalormorethan3timesthe baselinevalue,whicheverwashigher(Perrilloetal.,2015;Loketal., 1987).

Because of severe hepatic ﬂares may be characterized by increasedanti-HBcIgM,theriskofmisdiagnosisofacutehepatitis BinunknownHBsAgpositive-patientisrelevant.Clinicalhistory, highertitersofanti-HBcIgMandalowerviralloadcanhelpthe clinicianindifferentialdiagnosisbetweenacutehepatitisBanda ﬂareofchronicinfection.

Moreover,alsootherfactorssuchasdrugs,superinfectionswith otherhepatitisviruses,tumorinﬁltrationandsystemicinfections

cancauseanincreaseofALTlevelsandshouldbeconsideredinthe clinicaldecision-making.

Inthethirdstageofreactivation,liverinjuryisrecoveredand virusmarkersnormalize.

The risk of HBV reactivation in cancer patients receiving chemotherapy is inﬂuenced by predisposing factors related to the virus, the host and speciﬁc immunosuppressive treatment, althoughthecompletemagnitudeofriskisunknown.

ViralfactorsarerepresentedbyHBsAgandHBeAg seropositiv-ity,thepresenceofBgenotypeofthevirusandaboveallbyahigh HBVDNA level (>10 ˆ5copies/mL); hostpredisposingfactorsare malesex,youngage,highALTserumlevelsatbaselineandabsence ordecreaseofanti-HBslevelsduringtheanticancertreatment(Yeo etal.,2003;Lauetal.,2002;Yeoetal.,2004b).

Thetypeofchemotherapyandtheconcomitantuseof gluco-corticoidsareotherriskfactors;notably,theuseofanthracyclines, cyclophosphamide and vinca alkaloids is associated with an increasedriskofreactivation(Yeoetal.,2004b).Inparticular, epiru-bicinseemstoupregulatetheinvitroHBVreplicationlevelsand thepathologicaleffectsofHBV(Xuetal.,2014).Itfollowsthatthe chemotherapycombinationAC(doxorubicin-cyclophosphamide) intheadjuvantsettingofbreastcancerisoneofthemost predis-posingtherapeuticregimenforHBVreactivation.

TheassociationwithHBVreactivationisreportedalsofor gem-citabine(Cheongetal.,2003)andeverolimus,oneofthetargeted therapiesapprovedforbreastcancertreatment(Sezginetal.,2013). 6. ProphylaxisandtreatmentofHBVreactivation:thestate oftheart

FormanagingapossibleHBVreactivationduringchemotherapy, thecliniciancouldadopttwodifferentstrategies:toemploya pro-phylactictreatmentforhighriskpatientsortoprescribeanantiviral therapywhenreactivationisdetected.However,thesecond strat-egycouldleadtoanearlydiscontinuationofchemotherapyand itdoesnotusuallystopliverdamagecausedbyviralreactivation (Yunetal.,2011;Yeoetal.,2004c).

Lamivudine,anoralnucleosidereversetranscriptaseinhibitor, isindicated in treatmentofchronic hepatitisBassociated with evidenceofviralreplicationandactiveliverinﬂammation.

Manyliteraturedatashowedabeneﬁtfromprophylactic antivi-raltreatmentincancerpatientsatriskforHBVreactivation(Hsu etal.,2014;Leawetal.,2004;Martyaketal.,2008;Loombaetal., 2008).Mostofthestudieswerelimitedonpreventiveuseof lamivu-dineandbasedonhematologicpatients,howeverfewstudieswere conductedonpatientswithsolid tumors,especiallywithbreast cancer.

Ameta-analysisof14studiesinvolving275patientsundergoing chemotherapyforhematologicalorsolidmalignanciesfoundthat prophylacticlamivudinereducedtheriskofHBVreactivationand theincidenceand severityof HBV-relatedhepatitisby80–100% (Loombaetal.,2008).

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severity of hepatic dysfunction and the incidence of hepatitis ﬂare-upduringchemotherapycomparedwithpatientsreceiving therapeutic antiviral treatment at the onset of increasing liver enzymes.

Amorerecentmetanalysis(Liuetal.,2015)regarding HBsAg-positive breast cancer patients demonstrated that lamivudine prophylaxis had a signiﬁcant reduction in the risk of HBV reactivation (RR=0.23, 95% CI: 0.13–0.39, p<0.00001) and the ratesof moderateand severehepatitis weresigniﬁcantlylower thanthepatientsgroupwithnoprophylaxis(RR=0.25, 95%CI: 0.1–0.62,p<0.003;RR=0.25,95%CI:0.1–0.59,p<0.0002). Further-more,patientsinlamivudine-prophylaxisgrouppresentedfewer chemotherapydisruptionsanddelays(RR=0.36,95%CI:0.21–0.64, p=0.0004;RR=0.42,95%CI:0.21–0.82,p=0.01).

Thereisclinicalevidencethatreservingtheuseoflamivudine inpatientswhodevelopALTelevationduetoHBVreactivationis noteffectivecomparedtoprophylacticstrategy.Thisﬁndingcan beexplainedbythebiologyofviralreactivation:studiessuggested thatviralreplicationoccurs1–2weeksbeforehepatitisﬂare(Liaw, 2003;YeoandJohnson,2006;Yeoetal.,2001;Lauetal.,2003; Kohrtetal.,2006),sotheprophylacticuseoflamivudinehavea clin-icalstrongerrationalthantherapeuticstrategy.Inthesepatients, despiteuseoflamivudine,thereportedmortalityisintherangeof 20–30%(DelaRevillaetal.,2013).

Duringchemotherapy,whenhepatitisBﬂareisdetected, antivi-raltreatmentshouldbestartedassoonaspossiblebecausethe effectsofantiviraltherapyarenotimmediateontheliverdamage. Animportantconcernrelatedtotheuseoflamivudineisthe potentialdevelopmentoflamivudine-resistancemutation (YMDD-mutations),related tohighHBVDNA levels(Torres andDavila, 2012)atbaselineandassociatedwithclinicalandbiochemicalﬂare (Tanetal.,2015).Becauseofthisresistance,lamivudinecouldbe ineffectivetopreventHBVreactivationandhepatitis,sothatitis appropriatetoavoidthisdruganduseotheronesinpatientswho needextendedperiodsofchemotherapy.Indeed,newerantiviral drugssuchasentecavir,tenofovir,adefovirandtelbivudinearenow available.Expertsrecommendedtheuseoflamivudineor telbivu-dineifthedurationoftreatmentisnolongerthan12monthsand HBVDNAlevelsatbaselinearelow.Ontheotherhand,entecavir (Watanabeetal.,2010)ortenofovirshouldreplacelamivudinefor patientswhorequirelongerdurationofprophylaxis(morethan12 months)orhavehigherHBVDNAtiters(DelaRevillaetal.,2013). On thebasis of recent guidelines (EuropeanAssociation For The Study Of The Liver, 2012), the prophylactic treatment of HBsAg-positivepatientsdependsonHBV-DNAload:if<2000UI/mL andthepatientisgoingtoreceiveaconventionalchemotherapy lamivudinecouldbeprescribed.Theprophylacticemploymentof entecavirortenofovirshouldbereservedtohematologicalpatients undergoingstem-celltransplantionormonoclonalantibody ther-apyandincaseofHBV-DNAload>2000UI/mL.

7. OccultHBVinfection:thehiddenenemy

TheprevalenceofoccultHBVinfection(OBI)variesfrom1%to 95%worldwide,accordingtoendemicity,cohortfactorsand sensi-tivityofdiagnostictechniques(Raimondoetal.,2008).

OBIischaracterizedbythepresenceofHBVDNAinlivertissue withundetectableorverylow(<200UI/ml)serumlevelsin HBsAg-negativepatients(KwakandKim,2014).WecanclassifyOBIinto seropositive(anti-HBcand/oranti-HBspositive)andseronegative (absenceofanti-HBcandanti-HBs)group(Squadritoetal.,2014; Coppolaetal.,2013;Hu,2002;Bréchotetal.,1998;Dosetal.,2014; TorbensonandThomas,2002;Raimondoetal.,2013).

The extraction of HBV DNA from theliver tissue would be thegoldstandardfordiagnosisofoccultHBVinfection.However,

serumHBVDNAassayisthemostcommonlyusedmethodfor diag-nosis,becauseofthebetterfeasibilityinroutineclinicalpractice despiteserumDNAissometimesundetectable(Raimondoetal., 2008).

InOBIcarrierspatients,HBVreactivationrepresentsarelevant clinical implication, particularly in immunosuppressed patients suchascancerones;OBIreactivationcouldcauseliverfailure, lead-ingtochemotherapydiscontinuationwithconsequentprogression ofthedisease,fulminanthepatitisandlife-threateningconditions too(Schmeltzer and Sherman,2010; Coppolaet al., 2011).The highestriskofOBIreactivationoccursinhematologicpatients,in liverandhematopoieticstemcelltransplantationorin anti-CD20-treated patients(Squadritoet al.,2014; Raimondo et al.,2007; Peietal.,2010).Regardingsolidtumors,therearenotconclusive studiesaboutHBVreactivationinocculthepatitis, butsystemic chemotherapyhasbeenreportedaspossiblecauseofOBI reac-tivation(Raimondo et al.,2007; Saitta et al.,2013).The useof prophylactictreatmentinOBIpatientsisstilldebatedandbased onviralserologicalstatus,typeofcancerandchemoterapicdrugs (Sagnellietal.,2014);actually,theuseofantiviraltherapyis rec-ommendedonlyforpreviously-mentionedpatientsathighriskof reactivation,whileitisindicatedonlyALTandHBVDNA monitor-ingintheotherclinicalconditions(Squadritoetal.,2014;European AssociationForTheStudyOfTheLiver,2009;Barclayetal.,2008). Moreover,OBImaybeinvolvedinthetransmissionofinfection throughblooddonationsororgantransplantation;thissituation mayoccurswhenthedonorisanOBI-carrierorwhentheblood comesfromadonorinthewindowperiodofacuteHBVinfection. Moreover,thebloodcouldbeinfected withvariantviruses (so-calledS-escapemutants)notdetectablebytheavailablediagnostic HBsAgassays(CandottiandAllain,2009).

OtherclinicalimplicationisthepossibilityofHBVreactivation in OBI-carriers.Finally,occult HBVinfectionplaysa role in the progressionofchronicliverdiseasesandHCC,expeciallyinHCV patients.

Clinicians should payattention tothe presenceof OBI, par-ticularlyinimmunosuppressedclinicalconditionssuchascancer patientsundergoingchemotherapy.Furtherstudiesareneededto clarifyclinicalimplications,preventivemeasuresandthe manage-mentofoccultinfectionsinthiscategoryofpatients.

8. HBV:toscreenornotscreen

There is no evidence in determining the beneﬁt of routine screeningforchronicHBVinfectioninpatientundergoing cyto-toxic and immunosuppressive chemotherapy. Major guidelines (Hoofnagle,2009;DelaRevillaetal.,2013;EuropeanAssociation ForTheStudyOfTheLiver,2012;LokandMcMahon,2009;Artz etal., 2010;Weinbaumet al.,2008)(Table2)recommendHBV screeninginHBV-infectionhighriskpatientsorifthe immunosup-pressioncausedbythetreatmentisexpectedtobehigh(Table3). Apartfromthisgeneralrecommendation,theguidelines,giventhe inaccuraciesinascertainingrisksforHBVinfection,donot demon-strateunanimousconsentinofferingHBVscreeningforallpatients undergoingchemotherapy.Infact,ifpatientsreceiving chemother-apyareconsideredathighriskforreactivationofHBVperse,the screeningstrategyshouldbeuniversal.Furthermore,thereisno unanimous consent regarding serological tests: themajority of guidelinesrecommendscreeningwithHBsAgandanti-HBc,even thoughtheUnitedStatesCentersofDiseaseControlandPrevention (CDCP)considerascreeningmarkeralsoanti-HBs.

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pop-C. Bozza et al. / Critical Reviews in Oncology/Hematology 98 (2016) 137–146 <2000UI/mL

PatientswithHBVDNAbaselinevalue >2000UI/mLshouldcontinue treatmentasimmunocompetent patients.

used

Ifthetreatmentisexpectedtobe longerthan1yeartenofoviror entecavirarepreferred.

AvoidInterferonalphabecauseofthe bonemarrowsuppressiveeffect.

Artzetal.(2010) Insufﬁcientevidenceto determinethebeneﬁtsandthe harmsofroutinescreeningin patientsundergoinga chemotherapicor

immunosuppressivetreatment HBVscreeningrequiresclinical judgment

MaybeconsideredinHBVhigh riskpatientsorifhighly immunosuppressivetherapyis planned

HBsAg

Insomepopulations,testingfor antiHBcshouldalsobeconsidered Noevidencetosupportserologic testingforantiHBs

InHBVchronicpatients,anantiviraltreatment shouldbeconsideredtoreducetheriskofHBV reactivation,althoughevidenceislimited

– Screeningand/ortreatingshouldnot delaytheinitiationofchemotherapy

European AssociationForThe StudyOfTheLiver (2012)

Allcandidatesfor chemotherapyand

immunosoppressivetreatment HBsAg antiHBc

HBsAg-positivepatientsshouldreceive pre-emptiveantiviraltreatmentregardlessof HBVDNAlevel

HBsAg-negative,antiHBcpositivepatients withdetectableHBVDNAshouldbetreatedas HBsAgpositivepatients

HBsAg-negative,antiHBcpositivepatients withundetectableHBVDNAshouldbeclosely monitored

– Ifthetreatmentisexpectedtobeshort andbasalHBVDNAislowlamivudine andtelbivudinecanbeused Ifthetreatmentisexpectedtobe longerandbasalHBVDNAtenofoviror entecavirarepreferred

Hoofnagle(2009) Allpatientsundergoingcancer chemotherapyandmarked immunosuppressive treatments.

HBsAg antiHBc

HBsAg-positivepatientsshouldbeevaluated forindicationsforHBVtreatmentandstarted onappropriatetherapy

InactiveHBsAgcarriershouldreceiveantiviral prophylaxis

HBsAg-negative,antiHBcpositivepatientswith undetectableHBVDNAshouldbeconsidered forantiviraltreatmentifaggressiveorlong termchemotherapy/immunosuppressionare expected

InHBsAg-positivepatientstherapy shouldcontinueforaslongasrequired formanagementofunderlyingchronic disease

Inotherpatients,prophylaxisshould continueforatleastsixmonthsafter stoppingchemotherapy

–

Weinbaumetal. (2008)

Allpatientsneeding immunosoppressivetreatment shouldundergoserologic testing

HBsAg antiHBc antiHBs

AllpatientsHBsAg-positiveshouldreceive antiviralprophylaxis

PatientsantiHBc-positiveshouldbeclosely monitored

– –

DelaRevillaetal. (2013)

Allcandidatesfor chemotherapyshouldbe screenedforbeforeinitiation oftherapy

Forpeoplelivinginareasoflow prevalence,itmaybesufﬁcient toscreenonlythosepatients whobelongtohigh-riskgroups forHBVinfection

HBsAg antiHBc

AllpatientsHBsAg-positiveshouldreceive antiviralprophylaxis

HBVDNApositivepatientsshouldreceive antiviralprophylaxisaccordingtoHBVDNA levels,asforHBsAg-positivepatients HBsAg-negative,antiHBc-positivewithHBV DNAtestnegativeshouldbeclosely monitored,buttheyshouldbeconsideredfor antiviraltreatmentifaggressiveorlongterm chemotherapy/immunosuppressionare expected

PatientswithHBVDNAlevels>2000 UI/mLshouldbetreatedfromone weekbeforeinitiatingchemotherapy untilthesameendpointsusedfor immunocompetentpatients Patientswithundectectablelevelsor HBVDNA<2000UI/mLshould continuetreatmentfor12monthsafter cessationofchemotherapy

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Table3

IndividualsathighriskforHBVinfection.

Peopleborninthesecountriesathighorintermediateprevalenceratesofinfection:

Asia Africa EasternEurope

SouthandCentralAmerica TheArctic EuropeanMediterranean SouthPaciﬁcIsland MiddleEast

Otherpeoplerecommendedforscreening

PeopleborninlowHBVprevalencecountriesnotvaccinatedandwhoseparentswereborninhighprevalenceregion SexualcontactswithHBsAg-positiveperson

Inmatesofprison

Peoplewhohavemultiplesexualpartners PatientsinfectedwithHCVandHIV Peoplethathaveinjecteddrugs

Personsneedingimmunosuppressivetreatment

ulationandtheexpectedriskofimmunosuppressionlowerthan

haematologicalpatients.

Screeningstrategymaybeeconomicallyfavourableinselected

patientsandwithamoresimpleserologicalmarker,suchastheuse

ofonlyHBsAginadjuvantpatientsbutfurtherstudiesareneeded

inordertoconsiderthisscreeningapproachinclinicalpractice.

9. WhataboutHCV?

Hepatitis C virus (HCV) is one of the most important and

frequentcauseof chronichepatitis,cirrhosisand hepatocellular

carcinoma.PrevalenceofHCVinfectionsisreportedtobehigher

inhaematologicalmalignancies, inparticular inpatientswitha

diagnosisofNon-Hodgkin’slymphoma.

Inpatientswithsolidcancer,theincidenceofHCV-relatedliver

dysfunctionisnotwellestablishedbecauseoflimiteddatafrom

fewandretrospectivestudies(Morrowetal.,2010).

Whiletheknowledgefrompreviousresearchsupportsthe man-agementofhepatitisBduringthetreatmentofbreastcancer,little informationareavailableabouttreatmentofpatientswithsolid cancerandchronichepatitisC.

WeknowthatthereisacloserelationaboutHCVreplication and immunosuppressive therapy, such as chemotherapy treat-ment.Previousstudieshaveshownahighrateofchemotherapy discontinuationand hepatotoxicityin patientswith cancerand HCV-related hepatitis because of HCV reactivation due to an increasedHCVreplication(Mahaleetal.,2012).

HCVreactivationseemstobelesscommonthanHBV reactiva-tionandisgenerallyassociatedwithagoodoutcomeandlesssevere medicalconsequences.OnlyafewdeathsrelatedtoHCV reactiva-tionduringachemotherapytreatmenthavebeenreported.Despite thisreport,mortalityratesofHCV-infectedpatientswassimilarto thoseofHBV-infectedpatientswhenaseverehepatitisduetoa viralreactivationdeveloped(TorresandDavila,2012).

Currently,nodirectmethodstopredictpatient’s riskofHCV reactivationwaspointout.

RecommendationsfromCDCPsuggestscreeningwithabaseline anti-HCVtest,detectingspeciﬁcantibodiesagainstHCV(anti-HCV) beforestartingachemotherapytreatment(Hwangetal.,2014).

HCVreactivationcanbedeﬁnedasatleastathreefoldincrease inserumALTlevelina patientwithoutliverinvolvement(liver metastasisorprimarytumor),whodoesnotreceivehepatotoxicity drugsandhavenosystemicinfectionswiththeexceptionofHCV (DelaRevillaetal.,2013).

ThetimingofHCVreactivationcausedtoachemotherapydrug administrationcouldvary.AcuteexacerbationofHCVinfectioncan occurduringthecytotoxictreatmentbutusuallyitwasobserved weeksormonthsafterthelastdrugadministration.Noclinically symptomaticacuteALTorHCVRNAlevelselevationwasseenin

themostpatientswithHCVreactivationandusuallyliverenzymes elevationwasmildandtransient.

Patients with evidence of HCV infection (anti-HCV positive and/orHCVRNApositive)shouldbeclosely monitoredfor liver enzymesduringandafterchemotherapy.MonitoringALTevery1–2 weeksandHCVRNAevery4weeksduringchemotherapyandfor atleast3monthsaftertreatmentendisrecommended.IfALTlevel increasemorethan3foldfrombaselineit’snecessarytoestablisha closesupervisioninHCVRNAlevels.Ifthereisatleast1logIU/mL increaseinHCVRNAcomparedtobaselineviralload,itis reason-abletoconsiderdiscontinuationofchemotherapyifincreasingof liverenzymesprecludestheuseofcytotoxicdrugs(DelaRevilla etal.,2013)(Fig.3).

Increasing of liver enzymes should be associated with the increase in HCV RNA levels,but this issue was poorly investi-gated.Moreover,fewstudiesdemonstratednonedirectcorrelation betweentransaminaseelevationandincreaseHCV-RNAlevels dur-ingchemotherapyinpatientswithbreastcancerandHCV-related hepatitis.Theseﬁndingssuggestthatelevationofliverenzymes couldberelatedtolivertoxicitycausedtocytotoxicdrugs(Miura etal.,2013).

Currently no speciﬁcdrugs for the preventionof HCV reac-tivation are available in patients with solid tumors during a chemotherapytreatmentandonlysupportivetherapyis consid-ered.TheriskofHCVreactivationcouldbereducedusinglower dosesofcytotoxicandimmunosuppressivedrug,closemonitoring ofliverenzymesandmeasuringHCVRNAlevelsearlyifapotential viralreactivationwassupposed.

Anti-HCVtherapyisavoidedduringchemotherapybecauseit canworsentoxicitycausedbycytotoxicdrugs,inparticular haema-tologicaladverseeffects.

Inaretrospectivecohortofpatientswithanearlybreastcancer andHCV-relatedhepatitis,thetreatmentwithanthracyclineswith orwithouttaxaneandtrastuzumabwasfeasibleeventhroughin approximatelyone-halfofpatientsitwasrequireddosereductions anddelaysduringthetherapy.Thereasonwasrelatedto complica-tionsorsideeffectsduetotreatmentandratherduetoelevations oftransaminases(Morrowetal.,2010).

Datafromliteraturerevealedthatinpatientswithsolid can-cer and HCV infection, the administration of targeted therapy suchasanti-HERtherapy(trastuzumab,pertuzumabandlapatinib), mTORinhibitors(everolimus),anti-epidermalgrowthfactor recep-tortherapies(cetuximab,panitumumab)seemedsafe(Yazicietal., 2014).

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Fig.3.AlgorithmformanagementofHCV-positivepatientswithcancer.

10. Conclusions:takestockofthesituation!

Duringimmunosuppressivetreatmentssuchaschemotherapy, reactivationofHBVinfectionisalife-threateningcomplicationthat canoccurinHBVactiveorinactivecarriersandinpatientswithOBI. Thereisaclinicalbeneﬁtderivingfromprophylacticantiviral treat-mentincancerpatientsatriskforHBVreactivation:lamivudineis thedrugofchoiceifDNAviralloadis<2000UI/mL,inothercases tenofovirorentecavirareindicated.Onthenotherside,thereisno evidenceindeterminingthebeneﬁtofroutinescreeningforchronic HBVinfectionin patientundergoingcytotoxicand immunosup-pressivechemotherapy:theuniversalscreeningforHBVinfection withHBsAgandanti-HBcinpatientswithsolidtumoursis proba-blynotacost-effectivestrategy.Underutilizationofscreeningfor

hepatitisBvirusandofprophylaxisforreactivationisfrequentin clinicalpractice,butitcanbeleadtohighratesofhospitalization, discontinuationofchemotherapy,liverfailureanddeath(Hwang etal.,2015).HCVreactivationseemstobelesscommonthanHBV reactivationandisgenerallyassociatedwithagoodoutcomeand lessseveremedicalconsequencesandcurrently,nodirect meth-odstopredictpatient’sriskofHCVreactivationwaspointout.No speciﬁcdrugsforthepreventionofHCVreactivationareavailable.

Conﬂictofinterest

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inﬂuencedbyanypharmacompany.Authorsdidnotreceiveany compensationforauthoringthemanuscript.Nowritingassistance wasprovided.

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Biographies

ClaudiaBozzareceivedherMedicalDegreein2011fromtheUniversityof Tri-este,Italy.Since2012,Dr.BozzaworksaspostgraduatestudentattheDepartment ofMedicalOncology,UniversityHospitalofUdine,Italy.Dr.Bozzaistheco-author ofdifferentpublicationsinpeer-reviewedjournalsandsheisamemberofItalian AssociationofMedicalOncology(AIOM).

MarikaCinauseroreceivedherMedicalDegreein2012fromtheUniversityof Udine,Italy.Since2013,Dr.Cinauseroworksaspostgraduatestudentatthe Depart-mentofMedicalOncology,UniversityHospitalofUdine,Italy.Dr.Cinauseroisthe co-authorofdifferentpublicationsinpeer-reviewedjournalsandsheisamember ofItalianAssociationofMedicalOncology(AIOM).

DonatellaIaconoreceivedherMedicalDegreein2010fromtheUniversityof Trieste,Italy.Since2011,Dr.Iaconoworksaspostgraduatestudentatthe Depart-mentofMedicalOncology,UniversityHospitalofUdine,Italy.Dr.Iaconoisthe co-authorofdifferentpublicationsinpeer-reviewedjournalsandsheisamember ofItalianAssociationofMedicalOncology(AIOM).