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Contents

I. Epidemiology and natural course of HBV infection ............................................................ 277 1.PrevalenceofchronichepatitisB........................................................................................ 277 2.Modesoftransmissionandriskfactors............................................................................... 277 3.Genotypes............................................................................................................................ 278 4.EpidemiologyofHBVinfectioninHIV-infectedpatients.................................................. 278 5.NaturalcourseofHBVinfection........................................................................................ 278 5.1.ComplicationsofchronichepatitisB........................................................................... 278 5.2.EvolutionaryphasesofchronichepatitisB................................................................. 279 6.ReciprocalimpactofHIVandHBV................................................................................... 280 6.1.ImpactofHIVinfectiononHBVdiseaseprogression................................................ 280 6.2.ImpactofHBVinfectiononHIVdiseaseprogression................................................ 280

II. Identification of HBV/HIV .................................................................................................... 281 1.AssessmentofHBVriskanddiagnosisofhepatitisBinHIV-infectedpatients................ 281 1.1.InitiallaboratoryassessmentofHBVstatus................................................................ 281 1.2.EvaluationofHBVdiseaseseverity............................................................................ 281 1.2.1.Clinicalevaluationforsignsandsymptomsofadvancedliverdisease............. 281 1.2.2.ALTlevel............................................................................................................ 282 1.2.3.DeterminationofHBeAg.................................................................................... 282 1.2.4.HBVDNAlevel.................................................................................................. 282 1.2.5.Ultrasoundandotherevaluations....................................................................... 283 1.2.6.Histologicalevaluation....................................................................................... 283 1.2.7.Clinicalsituationsnotrequiringhistologicalevaluation.................................... 284 2.Evaluationofcomorbiditiesandco-conditions.................................................................. 284 2.1.Psychiatricdisorders.................................................................................................... 284 2.2.Alcoholabuse............................................................................................................... 284 2.3.Druguse....................................................................................................................... 284 2.4.Othercomorbiditiesandco-conditions........................................................................ 285 3.AssessmentofHIVriskanddiagnosisofHIV/AIDSinHBVpatients.............................. 285

III. Clinical management of HBV/HIV patients ...................................................................... 286 1.Coinfectedpatientsnotrequiringtreatment........................................................................ 286 2.CoinfectedpatientsrequiringonlyhepatitisBtreatment................................................... 286 2.1.Anti-HBVdrugsfortreatmentofhepatitisBinHIV-coinfectedpatientsnot requiringART(dosesandschedules)........................................................................... 287 2.1.1.IFNandPEG-IFN............................................................................................... 287 2.1.2.Adefovir.............................................................................................................. 287 2.2.EvaluationandtreatmentalgorithmsforchronichepatitisBinHIV-infected patientsnotrequiringART........................................................................................... 288 2.2.1.Algorithm1......................................................................................................... 288 2.2.2.Algorithm2......................................................................................................... 289 2.2.3.TreatmentoptionsforHBV/HIV-coinfectedpatientswith decompensatedliverdisease................................................................................ 290 3.CoinfectedpatientsrequiringonlyHIVorbothhepatitisBandHIVtreatment................ 290 3.1.ConsiderationsregardingtreatmentofhepatitisB...................................................... 290 3.1.1.SymptomaticpatientswithaCD4countof200–350cells/mm3........................ 290 3.1.2.PatientswithCD4count<200cells/mm3........................................................... 290 3.1.3.HIV-infectedpatientswithclinicalevidenceofcirrhosis................................... 290

3.2.ConsiderationsregardingtreatmentofHIVinfection................................................. 290 3.2.1.InitiationofHAART........................................................................................... 290 3.2.2.FirstlineHAARTregimens................................................................................ 291 3.2.3.SecondlineHAARTregimens...................................................................................... 2913.3.HIV-infectedpatientswith3TC-resistantHBVstrains......................................................... 291 4.MonitoringandevaluationofHBV/HIV-coinfectedpatients............................................. 292 4.1.HepatitisBtreatmentresponse.................................................................................... 292 4.1.1.MonitoringofHBVDNA................................................................................... 292 4.1.2.MonitoringofALT.............................................................................................. 292 4.2.MonitoringandevaluationofARTinHBV/HIV-coinfectedpatients......................... 292 4.3.Monitoringofadherencetotreatment......................................................................... 292 4.4.Managementofhepatotoxicity.................................................................................... 293 4.4.1.ImmunereconstitutioninHBV/HIV-coinfectedpatients................................... 293 4.4.2.Drug-relatedhepatotoxicity................................................................................ 293 4.4.3.HepatotoxicityofTBdrugsinthecontextofchronicHBVinfection............... 294

IV. Suggested minimum data to be collected at the clinical level ........................................... 295

References .................................................................................................................................... 296

management of hepatitis b and hiv coinfection

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I. Epidemiology and natural course of HBV infection

1. Prevalence of chronic hepatitis BApproximately400millionpeopleworldwidearechronicallyinfectedwiththehepatitisBvirus(HBV),andapproximately1milliondieannuallyofHBV-relateddisease.Theworldwidepreva-lenceofhepatitisBvirusrangesfrom0.1%to20%(1).Thiswiderangeislargelyduetodifferencesinageatthetimeofinfection.FollowingacuteHBVinfection,theriskofdevelopingchronicinfec-tionvariesinverselywithage:90%forperinatalinfection,25–50%forinfectionatage1–5yearsand1–5%forallothers(2).

About 45% of the world population live in areas where chronic HBV is highly endemic (≥8% of thepopulationhavethehepatitisBsurfaceantigen(HBsAg),43%liveinintermediate-endemicityareas(2–7%HBsAg-positive)and12%liveinlow-endemicityareas(0.6%to<2%HBsAg-posi-tive).IntermediatelyendemicareasincludeeasternandsouthernEuropeandtheRussianFedera-tion,whilenorthernandwesternEuropehavelowendemicity(seeTable1).

Table 1. Prevalence of hepatitis (2)

Areas of endemicity Prevalence of HBV carriers Predominant modes of transmission

Central Asian republics, parts of eastern Europe High (≥8%) Perinatal

Childhood(horizontal)

Western and northern Europe Low(<2%) SexualcontactInjectingdruguse

Other countries Intermediate(2–7%) Earlychildhood(horizontal)

2. Modes of transmission and risk factorsHBVisdetected inbloodandbody fluids (semen, saliva,nasopharyngeal fluids), and it canbetransmittedeithersexuallyorbyexposuretoinfectedbloodorfluids.Therearefourmajormodesoftransmission:• sexualcontact• mother-to-childtransmissionatbirth• parenteral(blood-to-blood)• throughotherinfectedbodilyfluids.

Theworld’spredominantmodeofHBVtransmissionisperinatal.IfapregnantwomanisanHBVcarrierandisalsohepatitisBeantigen(HBeAg)-positive,hernewbornbabyhasa90%likelihoodofbeinginfectedandbecominganHBVcarrier.Ofthesechildren,25%willdielaterfromchronicliverdiseaseorlivercancer(2). OtherriskfactorsfavouringHBVtransmissioninclude:• receivingbloodand/orbloodproducts• drug-injecting,tattoosandotherskin-piercingactivities• unprotectedpenetrativesex,inparticularanalandvaginalsex• organtransplants• healthcareoccupationalrisks• haemodialysis.

In low-endemicityareas, thehighest incidenceofHBVinfection isamongteenagersandyoungadults.Themostcommonmodesoftransmissionamongthesetwogroupsaresexualtransmissionandblood-to-bloodtransmissionduetoinjectingpractices(2).

hiv/aids tReatment and caRe cLinicaL pRotocoLs foR the Who eURopean Region

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Livercancer(HCC)

Acute infection

Chronic infection Cirrhosis

Liver transplanta-tion

Death

Liverdecompen- sation

>90%ofchildren

<5%ofadults(7)

23%in5years(8)

30%(7)

5–10%(7, 9)

HCC:hepatocellularcarcinoma.

3. GenotypesHBVisclassifiedinsevenmajorgenotypes,A–G.GenotypesAandDarethemostcommontypesinEurope.TheseroconversionratesofhepatitisBeantigen(HBeAg)andtheratesofmorbidityandmortalityrelatedtoliverdiseasearesimilarinpatientswithgenotypesAandD.However,sustainedbiochemicalandvirologicalremissionaremorecommoninpatientswithgenotypeAwhohavehadHBeAgseroconversionthaninthecorrespondinggenotypeDpatients (3).NocorrelationbetweenHBVgenotypesandresponsetolamivudineoradefovirtreatmenthasbeendemonstrated,asithasbeenwithinterferon.

4. Epidemiology of HBV infection in HIV-infected patientsHBVandHIVhavecommonroutesoftransmissionandendemicareas,butHBVisabout100timesmoreinfectious.Consequently,morethan70%ofHIV-infectedpeoplehaveabloodmarkerofpastorpresentHBVinfection(2, 4).Menwhohavesexwithmen(MSM)showhigherratesofHBV/HIVcoinfectionthaninjectingdrugusers(IDUs)orheterosexuals (5).TheriskofchronichepatitisBisgreaterincasesofHBV/HIVcoinfectionandcongenitaloracquiredimmunosuppressionasaresultoflymphoproliferativedisease,immunosuppressantdrugsormaintenancehaemodialysis.HBV-relatedliverdiseases(includingcirrhosisanditscomplications)ismoreprogressiveincasesofHIVcoinfectionthaninmonoinfection(6).

5. Natural course of HBV infectionAfteranacuteHBVinfectionacquiredinadulthood,90–95%ofadultsdevelopabroad,multispe-cificcellularimmuneresponsethateliminatesthevirusandultimatelyleadstothedevelopmentofprotectiveantibodiesforhepatitisBsurfaceantigen(HBsAg).Lessthan1%ofthosewhohavehadanacuteinfectiondevelopafulminanthepatitis,andtheremaining5–10%becomechronicallyinfected(2).

5.1. Complications of chronic hepatitis BAfteranaverageof30years,30%ofpatientswithchronicactivehepatitisBwillprogresstocir-rhosis.LiverfailuredecompensationoccursinaboutonequarterofcirrhoticpatientswithhepatitisBoverafive-yearperiod;another5–10%willgoontodeveloplivercancer(seeFig.1).Withouttreatment,approximately15%ofpatientswithcirrhosiswilldiewithin5years.

Fig. 1 . Natural course of chronic HBV infection


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AnumberofpatientswithchronichepatitisBwilldevelophepatocellularcarcinoma(HCC).ThoseatincreasedriskfordevelopingHCCincludeadultmaleswithcirrhosiswhocontractedhepatitisBinearlychildhood.Between60%and90%ofHCCpatientshaveunderlyingcirrhosis,butonly5%withcirrhosiswilldevelopHCC.Upto80%oflivercancersintheworldareduetoHBV.ThemediansurvivalfrequencyofHCCpatientsis<3monthswithoutappropriatetreatment,whichin-cludessurgery,percutaneoustreatments,hepaticirradiationandchemotherapy(2).

5.2. Evolutionary phases of chronic hepatitis BChronichepatitisBgenerallydevelopsovermanyyears,duringwhichtimepatientspassthroughanumberofphases,asillustratedinFig.2below(2).• TheimmunotolerantphaseoccursinyoungerindividualswhoareHBeAg-positive,haveahigh

HBVdeoxyribonucleicacid(DNA)levels(2x104–2x108IU/ml),andpersistentlynormalala-nineaminotransferase(ALT)levels.

• TheimmunoactivephasewithHBeAg-positiveorHBeAg-negativechronichepatitisB,mildHBVDNAlevels(2x103–2x107IU/ml)andpersistentlyelevatedALTlevels;thepatientisattimessymptomatic.

• Thenon-replicativephase,correspondingtoinactiveHBsAgcarriers.DuringHBeAgserocon-version,beitspontaneousorunderpressurefromtreatment,thereisaninactiveHBsAgcarrierstateinwhichHBeAgisnegative.Duringthisperiod,HBVDNAistypically<2x103IU/ml(oftenundetectable),withanormalormildlyelevatedALTlevel.Asmallnumberoflong-estab-lishedchroniccarriersapparentlyterminatetheiractiveinfectionandbecomeHBsAg-negative(upto1%peryear)(7).

Fig. 2. Evolutionary phases of chronic hepatitis B infection (2)

InactivePhase

Immunoactive PhaseTolerance

DNA

ALT

Cure

Anti-HBeAbHBeAg

HBsAg Anti-HBs

ALT:alanineaminotransferase;DNA:deoxyribonucleicacid;HBeAb:hepatitisBeantibody;HBeAg:hepatitisBeantigen;HBsAb:hepatitisBsurfaceantibody;HBsAg:hepatitisBsurfaceantigen.

HBVinfectioninadultsgenerallyconsistsof:• anearlyreplicativephasewithactiveliverdisease(HBeAg-positivechronichepatitisB)• alatelow-ornon-replicativephasewithHBeAgseroconversion• remissionorinactivationofliverdisease.

SeroconversionfromHBeAgtohepatitisBeantibody(HBeAb),eitherspontaneouslyorwithtreat-ment,istypicallyaccompaniedby:• adeclineinHBVDNAlevels(<19IU/mlor<105copies/ml)• normalizationofliverenzymes• resolutionofnecroinflammatoryactivityonliverhistology.


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TherateofspontaneousresolutionofactivereplicationandseroconversionfromHBeAgtoHBeAbis5–20%peryear.Duringthisprocess,someindividualsdevelopanescapevariant,aconsequenceofemergingmutationsintheprecoreregionthatdisruptsHBeAgproduction.TheseprecoreandcoremutantvirusesdevelopunderselectiveimmunepressureandareabletoretainhighlevelsofHBVreplication(8).Patients thusaffected–HBeAg-negativechronichepatitisBpatients–areclinically identifiedbytheabsenceofHBeAgandthepresenceofHBeAbandhighHBVDNAlevels.ThisparticularpatternismostcommonlyseenineasternAsiaandsouthernEuropebecauseofthehigherprevalenceofnon-Agenotypesthere,whichpredisposesthepopulationtothismuta-tion.

6. Reciprocal impact of HIV and HBV

6.1. Impact of HIV infection on HBV disease progression• HBVinfectionismorefrequentandmoresevereintheHIV-infected(6, 9).• InHBV/HIV-coinfectedpatients,necroinflammatoryactivity in the liver tends tobemilder,

buthigherHBVreplicationresultsinmoresevereliverfibrosiswithincreasedrisk(4.2timesgreater)forcirrhosiswithamorerapidprogressiontoend-stageliverdisease.

• InHBV/HIV-coinfectedpatientswithcirrhosis,hepatocellularcarcinoma(HCC)mayappearmoreaggressiveandatanearlieragethaninthosenotHIV-infected.Inaddition,itpresentswithmultifocallesionsmorefrequently(10).

• HIVappearstobeariskfactorforreactivationofhepatitisBinpatientswhohavedevelopedhepatitisBsurfaceantibodies(HBsAb,which60–70%ofHIV-infectedindividualshave),espe-ciallyinpatientswithsevereimmunodeficiency(11).

• PatientscoinfectedwithHIV1andHBV,especiallythosewithlowCD4+nadircounts,areatincreasedriskforliver-relatedmortality.

6.2. Impact of HBV infection on HIV disease progression• ThemajorityoftheclinicalstudiesthathaveexaminedtheinfluenceofHBVonHIVdisease

progression and considerHBsAgamarkerof chronicHBV infectionhavenot been able toprovethatHBVhasanyroleinHIVdiseaseprogression(6).

• Thereis,however,anincreasedriskforliverdisease-relatedmorbidityandmortalityinhepati-tis-coinfectedHIVpatients,aswellasmorehepatotoxicityunderantiretroviraltreatmentregi-mensorwhenactivetreatmentfrombothHIVandHBVisinterrupted.


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II. Identification of HBV/HIV

1. Assessment of HBV risk and diagnosis of hepatitis B in HIV-infected patients

1.1. Initial laboratory assessment of HBV statusAllHIV-infectedpatientsshouldbe:• testedforHBsAg(thepresenceofHBsAgforaminimumof6monthsindicateschronichepa-

titisB);• testedforhepatitisBcoreantibodies(HBcAb);and• assessedforpreviousHBVvaccination(HBsAb).

HBcAbalonewithoutHBsAgcouldbeduetoocculthepatitis.Inthisraresituation,HBVDNAisrecommended(seebelow).

1.2. Evaluation of HBV disease severityFurther evaluation is essential formaking a decision regarding treatment, focusing on in-depthlaboratorydiagnosisandclinicalevaluation.

1.2.1. Clinical evaluation for signs and symptoms of advanced liver disease

Examinationforsignsandsymptomsofliverdiseaseisrequired.Thepresenceorabsenceofclini-calevidenceforcirrhosismightbethekeyissueindefiningtreatmentstrategyinHBV/HIV-coin-fectedpatients.Theclinicalsignsofcirrhosisare:• enlargementanddysmorphyoftheliver;• portalhypertension(hepaticencephalopathy,digestivehaemorrhageduetooesophagealvarices

andsplenomegaly);• vascularspiders,palmarerythemaanddigitalhippocratism(mostlyinalcoholiclivercirrhosis

ratherthanvirallivercirrhosis);and• jaundice,ascites,oedemaandatendencytobleed.

TheChild-Pughclassificationisasimple,convenientprognosticmeasureinpatientswithlivercir-rhosis(seeTable2).Itmaybeusedtopredictpatientsurvivalratesandisinterpretedthus:• ClassA(5–6points)→compensatedcirrhosis• ClassB(7–9points)→compensatedcirrhosis• ClassC(10–15points)→decompensatedcirrhosis.

Table 2. Child-Pugh classification

Clinical and biochemical parameters

PoINts

1 2 3

Bilirubin<2mg/dl

(<34µmol/l)2–3mg/dl

(34–50µmol/l)>3mg/dl

(>50µmol/l)

Albumin >3.5g/dl 2.8–3.5g/dl <2.8g/dl

Ascites Absent Moderatea Severe/refractoryb

Encephalopathy Absent Moderate(stageI–II) Severe(stageIII–IV)

Prothrombin timec >60% 40–60% <40%aControlledmedically.bpoorlycontrolled.cnowreplacedinsomeEuropeancountriesbyinternationalnormalizedratio(INR)withthefollowingChild-Pughvalues:INR<1.70=1point;1.71–2.20=2points;>2.20=3points.Source:PughRNHetal.(12).


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1.2.2. ALt level

• Serialmeasurementsarepreferred,asALTmayfluctuatesignificantly.• ElevatedALTisamarkerofliverinflammation.• AnALTlevelthreetimestheuppernormallimitiscorrelatedwithacirrhosisrisk.• NormalALTlevelscanalsobeassociatedwithliverdiseaseprogression,particularlyinHBeAg-

negativepatients.• Liverenzymesshouldbemonitoredonaregularbasis,everysixmonthsfornormalALTlev-

els.Ifliverenzymesbecomeabnormalforaperiodofatleastthreemonths,HBVtreatmentisrequired.

1.2.3. Determination of HBeAg

• HBeAg-positivepatientsalmost invariablyhavehighHBVDNAlevels independentof theirALTlevels.

• HbeAg-negativepatientsmayalsohaveprogressiveliverdisease.• However,inbothsituationsdetectionandmeasurementofHBVDNAshouldbeperformed,as

combiningserologicaltestresultswithDNAlevelscandeterminetreatmentstrategy.Inlimited-accesssettings,HBVDNAdeterminationshouldbeprivileged.

1.2.4. HBV DNA level

• Resultsshouldbeexpressedininternationalunits(IU)permillilitre(1.0IU=5.4–5.8copies/ml,dependingonassay),theWHOstandardizedquantificationunitforHBVDNA,andindecimallogarithm(log10)IU/mlforpreciseassessmentofbaselineandsignificantHBVDNAchangesupontreatment.

• IfHBVDNAisinitiallyfoundtobe<2000IU/ml,especiallyinpatientswithelevatedALTorothersignsofliverdisease,serialmeasurementsshouldbeundertakenat leastsemiannually,sincesuchpatientsmayexhibitwidefluctuationsinHBVDNA.

• Differenttestsproducedifferentabsoluteresults;consequently,thethresholdsgivenforthera-peuticgoalscanonlybeindicative.

• AsingletypeofHBVDNAassayshouldbeusedformonitoringapatient.Ifachangeofassayisplanned,bothtestsshouldbeusedinparallelforatleasttwosubsequentsamples.

• IfonlyHBcAbispresentattheinitialassessment,itmaybeindicativeofoccultHBVinfection(seeTable3).OccultHBVisusuallyassumedwhenHBVDNAisdetectedat lowlevelsbyhighlysensitivetechniquesandintheabsenceofHBsAg.OccultHBVisfoundmorefrequentlyinHIV-positivepatientsthaninHIV-negativepatients,butitsclinicalrelevanceisuncertain.Currently,thereisnoevidencefortheneedtoroutinelydetectortreatoccultHBV.

Table 3. Classification of chronic hepatitis B virus infections based on laboratory determinants (13)

HBsAg HBsAb HBcAb HBeAg HBeAb HBV DNA

Chronic active hepatitis B

HBeAg-positivepatients + – + + – +HBeAg-negativepatientsa + – + – + +Occult HBV infection – – + – + +b

Inactive HBV carrier state + – + – + –

aPrecoremutantHBVstrain;bonlydetectedbypolymerasechainreaction(PCR)methods.

• PatientswithHBeAg-negativechronicHBVaredistinguishedfrominactiveHBVcarriersbythepresenceof>104HBVDNAcopies/ml(or>2000IU/ml),elevatedALTandnecroinflam-matoryliverdisease.TheliteraturesuggeststhatHBeAg-negativechronichepatitisBentailsaparticularlyhighriskofprogressivehepaticfibrosis(14, 15).Incontrast,inactiveHBVcarriersusuallyhaveundetectableHBVDNA.


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1.2.5. Ultrasound and other evaluations

Ultrasoundexaminationoftheliver(ifpossibleDopplerultrasoundexamination)canreveal:• cirrhosis:dysmorphyoftheliver• steatosis:hyperechogenicliver• possiblyearlyHCC:nodularuniqueorrarelymultiplelesions.

Whereavailable,patientswithlivercirrhosisshouldalsohave:• serumalpha-fetoprotein(AFP)assessmenttodetectHCC;and• uppergastrointestinalendoscopyfordetectingthepresenceofoesophagealvarices(withrisk

forgastrointestinalbleeding).

In the presence of significant oesophageal varices, prevention of bleeding by non-cardioselec-tivebetablockersisrecommended.Themostfrequentlyprescribeddrugispropanololatadosageallowingapulsereductionofatleast25–30%(40–160mgdailymaybenecessary)(16).

1.2.6. Histological evaluation

Thereareanumberofadvantagesofliverbiopsy,including:• wideavailability;• assessmentofnecrosis,inflammationandfibrosis;• eliminationofothercausesofliverdamage(opportunisticagents,drugtoxicity,alcohol,steato-

sis,etc.);• assessmentofpatientswithconsistentlynormalALTlevelswhoareHBV/HIV-coinfectedand

havelivercirrhosis.

Activityandfibrosisaretwomajorhistologicalfeaturesofchronichepatitisincludedinproposedclassifications. Interpretation of liver biopsies using the Metavir scoring system (see Table 4)improvesconsistencyintheinterpretationofhepaticfibrosis,withasomewhatweakerreproduc-ibilityforthehepaticinflammationgrade.Thefibrosisstageandinflammatorygradearecorrelatedintwothirdsofpatients.

Table 4. Metavir classification: activity and fibrosis scoring (17)

Activity score (A)Lobular necrosis

Absent (0) Moderate (1) Severe (2)

Parcellar necrosis

Absent (0) A0 A1 A2Minimal (1) A1 A1 A2Moderate (2) A2 A2 A3Severe (3) A3 A3 A3

A0=nohistologicalactivity;A1=minimalactivity;A2=moderateactivity;A3=severeactivity.

Table 4a.

Fibrosis score (F)F0: absence of portal fibrosisF1: stellar portal fibrosis with no septaF2: portal fibrosis with some septaF3:manyseptabutnocirrhosisF4:cirrhosis

Source:Simmondsetal.(18).


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Noninvasivemethodsformeasuringmarkersoffibrosis(suchasFibroTestTM)orliverstiffness(suchasFibroScanTM)havebeenshowntoprovideanadequateestimateoftheextentoffibrosis.Ifthesemethodsareavailable,theycansubstituteforperformingaliverbiopsy(19-22) (seeTable4a).

SeesectionIIIbelowfortwoalgorithmsforHBVdiagnosisinHIV-infectedpatients,aswellastreatmentoptionsforcoinfectedpatients.

1.2.7. Clinical situations not requiring histological evaluation

Decision to initiateHBVtreatmentdoesnotrequirehistologicalevaluationforeverypatient. Inparticular,HBVtreatmentmaybeconsideredwithoutaliverbiopsywhen:• thereareclinicalsignsofcirrhosis;• theCD4countis<350cells/mm3andantiretroviraltreatmentisindicated(seesectionIII.3.1

below);or• therearenoclinicalsignsofcirrhosisandtheCD4countis>350cells/mm3,ALTismorethan

twicethenormalupperlimitandHBeAgispositive.

2. Evaluation of comorbidities and co-conditions

2.1. Psychiatric disorders• PsychiatricdisordersarenotacontraindicationforHBVtreatment.• Patientsneedinginterferon(IFN)shouldbeevaluatedforpsychiatricdisorders.IFNshouldbe

avoidedforpatientswithacutepsychiatricdisorders,anddeferredforpatientswithmoderatetoseveredepressionuntiltheconditionimproves.

2.2. Alcohol abuse• Assessmentofalcoholintakeisanimportantpartofevaluation(seeProtocol6,Management of

hepatitis C and HIV coinfection, Annex3).• Heavy alcohol intake (≥50 g/day) contributes to fibrosis of the liver and can be identified by

biopsyinpatientswithHBVindependentlyofotherpredictors.Thisintakeisequivalenttofiveormoredrinksperday.Onedrinkisdefinedas330ml(12oz)ofbeer,150ml(5oz)ofwine,or38ml(1.25oz)ofhardliquor,containingapproximately10gramsofalcohol.

• Thereisevidenceofasynergistic(morethanadditive)interactionbetweenheavyalcoholcon-sumption (≥80 ml/day) and chronic HBV or hepatitis C virus (HCV) infections (23).

• AlcoholconsumptionincreasesHBVreplication,acceleratesfibrogenesisandliverdiseasepro-gressioninhepatitisBandC,aswellasdiminishingtheresponseandadherencetoanti-hepatitistreatment(especiallyifconsumptionis>50g/day).

• Activealcoholintakeisconsideredarelativecontraindicationforinterferon-basedtreatment.Thisrecommendationisbasedonthedocumentednon-complianceofheavydrinkerswithvari-ousmedical therapies,andthefact that theside-effectsof interferontreatmentalreadymakecomplianceextremelydifficult(24).

• Psychological,socialandmedicalsupportshouldbeofferedtostopalcoholintakeorreduceittounder10g/day.

2.3. Drug use• Patientsonopioidsubstitutiontherapyshouldnotbeexcludedfromtreatment.• InitiationofHBVtreatmentinactivedrugusersshouldbeconsideredonacase-by-casebasis

(seeProtocol5,HIV/AIDS treatment and care for injecting drug users).• Psychological and social support by a multidisciplinary team should be provided for such

patients.


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2.4. other comorbidities and co-conditionsTestingforcomorbiditiesshouldincludeacomprehensivemedicalhistorythatfocusesoncofactorsassociatedwithmoreprogressiveliverinjury,anditshouldcoverotherviralliverdiseases,tuber-culosis (TB) (seeProtocol4,Management of tuberculosis and HIV coinfection) andpregnancy.Serologicaltestingforhepatitisdeltavirus(HDV)mightbesuggestedinchronicallyHBV-infectedpatients,especiallyIDUs.IncaseofpersistentelevatedALTdespitecorrectHBVtreatment,pe-gylatedinterferon(PEG-IFN)canbeaddedtoantiretrovirals(ARVs),butefficacyandtolerabilityhavenotbeenassessedinHIV-coinfectedcases(25).

3. Assessment of HIV risk and diagnosis of HIV/AIDs in HBV patientsAllpatientswithHBVshouldbeofferedHIVtestingandcounsellingbecausetheinfectionsshareroutesoftransmission,andbecauseHIVacceleratesHBVprogression.Healthcareprovidersshouldexplaintopatientsthereasonsforofferingthetestanditsimportanceforcorrectclinicalmanage-ment.However,apatienthasarighttorefuseanHIVtest.

TheinitialassessmentofHIVstatusshouldinclude:• pretestcounselling;• serologicaltests(typically,enzyme-linkedimmunosorbentassay(ELISA)and/orrapidtests)for

HIVantibodies,followedbyawesternblotconfirmatorytest;and• post-testcounsellingirrespectiveoftheresult,includinginformationonreducingriskybehav-

iour.

Further clinical evaluation of HIV-infected patients is required to develop a clinical manage-ment strategy for HBV/HIV-coinfected patients. For detailed information, see Protocol 1,Patient evaluation and antiretroviral treatment for adults and adolescents.


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III. Clinical management of HBV/HIV patients

Bytheendofthelaboratoryandclinicalevaluation,patientscanbeputintooneofthreetreatmentcategories:1. notrequiringhepatitisBorHIVtreatment2. requiringonlyhepatitisBtreatment3. requiringonlyHIVtreatmentorbothhepatitisBandHIVtreatment.

ForclinicalmanagementofpatientswithHBV/HIVcoinfectionthekeyissueisthetreatmentofHBVandHIVandastrategyfor its initiation.Thisdecisionshouldbebasedonanalysisof thefollowingparameters:• HBVDNAlevels• severityofliverdisease• CD4countandindicationsforantiretroviraltreatment(ART)• contraindications.

HBVtreatmentshouldbeconsideredforanyHBV/HIV-coinfectedpatientwithevidenceofactiveliverdisease(highALTlevel,significantserumHBVDNAlevel,necro-inflammationlesionsorfibrosisinliverbiopsy),irrespectiveoftheCD4count.

1. Coinfected patients not requiring treatmentThesepatientshavethefollowingstatus:• CD4 count of ≥350 cells/mm3;and• mildornotprogressingHBVdisease(HBVDNA<20000inHBeAg-positivepatients,orHBV

DNA<2000inHBeAg-negativepatients;normalALT;nosevereliverdiseaseifabiopsyhasbeenperformed).

Sincethereisnoimmediateneedfortreatment,thepatient’shealthshouldbecarefullymonitoredby:• aCD4counteverythreetosixmonths;• clinicalmonitoringofHIV-relatedsymptomseverythreetosixmonths;• ALT measurements every six months for patients with inactive HBV infection (since liver

diseasemayreactivateevenaftermanyyearsofquiescence),andAFPorultrasoundforHCC.• HBeAg-positivepatientswith elevatedALT levels and compensated liverdisease shouldbe

observedforthreetosixmonthsforspontaneousseroconversionfromHBeAgtoHBeAbpriortoinitiationoftreatment.

2. Coinfected patients requiring only hepatitis B treatmentHBV/HIV-coinfectedpatientsneedingonlyhepatitistreatmenthavethefollowingfeatures:• CD4countof>350cells/mm3;• HbeAg-positiveandHBVDNA>20000IU/ml,orHbeAg-negativeandHBVDNA>2000IU/

ml;• clinicalcirrhosisanddetectableHBVDNA(>200IU/ml);and• histologically proven active disease (Metavir score ≥A2 or F2), or persistently elevated ALT

levelsintheabsenceofothercausesofALTelevation.

2.1. Anti-HBV drugs for treatment of hepatitis B in HIV-coinfected patients not requiring ARt (doses and schedules)Sincenolarge-scalerandomizedcontrolledtrialshavebeenconductedtodeterminetheefficacyofanti-HBVdrugsinHBV/HIV-coinfectedpatients,recommendationsfortreatmentandmonitoring


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needtobederivedfromwhatdataareavailablepluswhatisalreadyknownaboutthetreatmentofHBVmono-infectedpatients.

Three antiviral drugs are recommended for use, PEG-IFN-α 2a, standard IFN-α 2a or 2b, and adefovir(ADF).

2.1.1. IFN and PEG-IFN

ThehighesteffectivenessofinterferonhasbeendemonstratedinpatientswithHBeAg,ALTlev-elsmorethantwicetheupperlimitofnormalandlowHBVDNAlevels.PEG-IFNisbecomingastandardtreatmentforHBV,anditisthepreferredoptioninpatientswiththesefeaturesandaCD4countof>500/mm3.

Dosage and administration of PEG-IFN-α 2a (26) are:• 180µg/weekfor48weeks,independentofHBeAg/HBeAbstatus.

Dosage of INF-α 2a or 2b (26) is:• forHBeAg-positivecases,10millionunits(MU)subcutaneous3timesweekly,or5MUdaily

for4–6months;and• forHbeAg-negativecases,samedosagefor12months.

2.1.1.1 ContraindicationsAbsolutecontraindicationsare:• pregnancyandbreastfeeding;• decompensatedliverdisease(duetoanincreasedriskforthrombopenia,deathfromliverfailure

orsepsis);• uncontrolledpsychiatricdisease;• significantleukopeniaorthrombocytopenia;• unstablecoronaryarterydisease,diabetesorhypertension;or• uncontrolledseizuredisorder.

Relativecontraindicationsare:• autoimmunediseases(e.g.psoriasisandrheumatoidarthritis)• priorhistoryofdepressionorpsychiatricillness.

2.1.2. Adefovir (ADF)

WithADF,anucleotideanalogue,aprogressiveandefficientsuppressionofHBVDNAisobserved.TherateofHBV-resistantstrainsisverylowintheshortterm(3%after2years)buthasrecentlybeenshowntobeashighas28%afterfiveyearsofmonotreatment(27).

ADF dosageis10mgorallyoncedaily(28).• Theoptimaldurationoftreatmentisindefiniteintheabsenceofothertreatment.• ItisrecommendedtocontinuetreatmentwithADFforatleast12months.• ADFdosageshouldbeadaptedtocreatinineclearance(CrCl): ° ifCrClis20–49ml/min,10mgevery48hours ° ifCrClis10–19ml/min,10mgevery72hours ° ifthepatientisonhaemodialysis,10mgevery7daysfollowingdialysis.

Contraindicationsarepregnancyandnephrotoxicity.


288

2.2. Evaluation and treatment algorithms for chronic hepatitis B in HIV-infected patients not requiring ARt

2.2.1. Algorithm 1

TheapproachinthisalgorithmfocusesonadeterminationofHBVDNA(intheabsenceofclinicalcirrhosis).SeeFig.3.

Fig. 3. Algorithm 1

CD4 >350 cells/mm3

HBV DNA Positive

HBeAg Positive HBeAg Negative

DNA ≤20 000 DNA >20 000 DNA >2000 DNA ≤2000

MonitoringLiver biopsy

Non-invasive markera Monitoring

Metavir score≥A2 and/or ≥F2

Metavir score<A2 and/or <F2

TreatmentPEG-IFN for HBeAg-positiveb

ADF for HBeAg-negativeb

TDF + 3TC(FTC) + EFVc

Monitoring

aNon-invasivemarkers:FibroTest-serummarkers,FibroScan-imagetechnique.bEitherPEG-IFNorADFisthechoiceforHBV/HIV-coinfectedpatientswhodonotneedART.ARTcanbeconsideredforpatientswithCD4countsof350–500cells/mm3ifPEG-IFN,IFNorADFarenotavailable.cPrematureuseofARTcanexposepatientstoARTside-effectsandariskofdevelopingHIVresistancetotenofovir(TDF)orlamivudine(3TC),whichcancompromisefutureART.

HBeAg


289

2.2.2. Algorithm 2

Thesecondalgorithm’sapproachisfocusedonclinicalevaluation,inparticularforsettingswhereHBVDNAisnotavailable.ThisapproachallowsidentifyingthoseHBV/HIV-coinfectedpatientsinneedofhepatitisBtreatmentforwhomadecisionregardingtreatmentcanbemadewithoutdeter-miningtheHBVDNAlevel(i.e.patientswithclinicalcirrhosis,andpatientswithnoclinicalsignsofcirrhosis,butwithelevatedALTlevelsandpositiveHBeAg).However,patientswithsuspectedchronichepatitisB(HBeAg-negativewithALTmorethantwicetheupperlimitofnormal)shouldbereferredtoahigherlevelofmedicalcareforevaluationofHBVDNAandtheappropriatecourseoftreatment.

Fig. 4. Algorithm 2

aPEG-IFNorADFisthebestchoiceforHBV/HIV-coinfectedpatientswhodonotneedART.ARTcanbeconsideredforpa-tientswithCD4countsof350–500cells/mm3ifIFNorADFarenotavailable.bPrematureuseofARTcanexposepatientstoARTside-effectsandariskofdevelopingHIVresistancetoTDFor3TC,whichcancompromisefutureART.cIncaseofnegativeHBeAg,thefurtherdiagnosticalgorithmisthesameasshowninAlgorithm1.

Clinical evidence of cir-rhosis

No clinical evidence of cirrhosis

ALT

>2 timesnormal

upper limit

<2 timesnormal

upper limit

HBeAg

HBeAg Positive HBeAg Negative

Monitoring

Refer toHBV DNAc

TreatmentPEG-IFN for HBeAg-positivea

ADF for HBeAg-negativea

TDF + 3TC(FTC) + EFVb

CD4 >350 cells/mm3


290

2.2.3. treatment options for HBV/HIV-coinfected patients with decompensated liver disease (29)

• Patientswithdecompensatedliverdiseaserequirelong-term,indefinitetreatment,asvirologicalrelapseafterdiscontinuationoftreatmentcanbeaccompaniedbyarapidclinicaldeterioration.

• ADF is safe inpatientswithdecompensated liverdisease, and is frequently associatedwithsignificantclinicalimprovement.Prolongedtreatmentis,however,associatedwith28%drugresistanceafterfiveyearsinmonoinfectedpatients.Thus,closemonitoringforHBVDNAisrecommendedeverysixmonthsinordertodetectdrugresistanceincaseofaviralloadincreaseofmorethan1log,inwhichcasegenotypingshouldbeperformed.Interferoniscontraindicatedinpatientswithdecompensatedliverdiseaseduetoitsverypoortolerabilityprofile.

3. Coinfected patients requiring only HIV or both hepatitis B and HIV treatment Forthesepatientsmedicationdecisionsarebasedonrecognitionofthedualeffectofsomeantiret-roviraldrugsonHBVandHIVviruses,suchaslamivudine(3TC)andtenofovir(TDF)(30-32).

3.1. Considerations regarding treatment of hepatitis B

3.1.1. symptomatic patients with a CD4 count of 200 – 350 cells/mm3

ThedecisiontotreatforHBVismainlybasedonHBVDNAlevels.• InHBeAg-positivepatientswithHBVDNA>20000IU/mlandHBeAg-negativepatientswith

HBVDNA>2000IU/ml,theARTregimenmustincludetwodual-activitydrugs(anti-HBVandanti-HIV).

• InpatientswithlowlevelsofHBVDNA,anARTregimencontainingtwodual-activitydrugsisoptionalbuthighlyrecommendedinanticipationofanearlyswitchduetoareactivationofhepatitis.

3.1.2. Patients with CD4 count <200 cells/mm3

WhenCD4countis<200cells/mm3andARThasbeeninitiatedthereisariskofaseverereactiva-tionofhepatitisBduring immunereconstitution,whichmay includea life-threateninghepatitisflare.IrrespectiveofindicationsforHBVtreatment,theARTregimenforthesepatientsmustthere-foreincludetwodual-activitydrugsinordertominimizetheriskofHBVreactivation.

3.1.3. HIV-infected patients with clinical evidence of cirrhosis

• Clinicalcirrhosisisanabsoluteindicationfortreatment.• TheHBVDNAthresholdforinitiationofHBVtreatmentislowerthaninpatientswithoutcir-

rhosis(over200IU/ml,i.e.assoonasdetectable).• Nomedicationsarecontraindicatedforpatientswithcompensatedcirrhosis.• Patientswithdecompensatedcirrhosisshouldbereferredforpalliativecare.• Patientswithcirrhosisrequireclinicalobservation,liverfunctionmonitoringanddrugmonitor-

ing.• ItmightbenecessarytoadjustthedoseofARVmetabolizedbytheliver.Ifthisisnotfeasible,

thendidanosine(ddI)andstavudine(d4T)havetobeavoidedandaregimenwithaproteaseinhibitor(PI)shouldbecloselymonitored(seeProtocol6,Management of hepatitis C and HIV coinfectionforrecommendationsonantiretroviraldosageadjustmentinpatientswithend-stageliverdisease(ESLD).

3.2. Considerations regarding treatment of HIV infection

3.2.1. Initiation of HAARt

InitiationofARTinHBV/HIV-coinfectedpatientsshouldfollowthecurrentrecommendationsforHIV-monoinfectedpatients(seeTable5).(Forfurtherdetails,pleaserefer toProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.)


291

Table 5. Recommendations for initiating HAART in HBV/HIV-coinfected patients

CD4 count Recommendations

≤200 cells/mm3 Antiretroviraltreatmentisrecommended.ARTregimensshouldcontaintwodual-activitydrugs(targetingbothHBVandHIV).

200–350cells/mm3

AntiretroviraltreatmentshouldbeconsideredwithahighviralloadorrapiddeclineinCD4count,butshouldbestartedbeforetheCD4countfallstolessthan200cells/mm3.IfHBVtreatmentisindicated,ARTregimenscontainingtwodual-activitydrugsarealsoindicatedorhighlyrecommended.

3.2.2. First line HAARt regimens

Table 6. First-line HAART for HBV/HIV-coinfected patients

ARV drug classes HAART regimens

Preferred first line 2NRTIs+1NNRTI TDFa+(3TCorFTCb)+EFVc

Alternative first line 3NRTIs ZDV+(3TCorFTCb)+TDF

aIfTDFisnotavailable,3TCshouldbeamandatorycomponentoftheregimen.b FTC is equivalent to 3TC and is available together with TDF as a fixed-dose combination (33, 34).cNevirapine(NVP)canbeconsideredinsteadofefavirenz(EFV)forpatientswithouthepaticdysfunctionandwithclosemoni-toring.ItshouldbeavoidedinwomenwithCD4count>250cells/mm3orinmenwithCD4count>400cells/mm3.

3.2.3. second line HAARt regimens

Table 7. Second-line HAART for HBV/HIV-coinfected patients

ARV drug classes HAART regimens

Note: TDFand3TCorFTCshouldbeutilizedforhepatitistreatmentinadditiontothesecond-lineHAART.

2NRTIs+1boostedPI

ABC+

(ddIord4Ta)+

(LPV/rorSQV/rorNFV)

1NNRTI+1NRTI+1boostedPIb

EFV+

(ABCord4Ta)+

(LPV/rorSQV/rorNFV)2PIs(1boosted) LPV/r+SQV

a If zidovudine (ZDV) was not used in the first line, d4T can be considered an option in second-line ART.bAnoptionalregimensupportedbyarecentstudyisLPV/r+EFV(35).

3.3. HIV-infected patients with 3tC-resistant HBV strains• 3TC(lamivudine)resistancedevelopsmorerapidlyinHBV/HIV-coinfectedpatients,andeven

atthehigherdoses(300mgdaily),itappearsinalmost50%and90%ofcoinfectedpatientsaftertwoandfouryears,respectively,of3TCtreatment (36, 37).

• Inthepresenceofsuspectedlamivudineresistance,thefirststepistoconfirmit,ifresistancetestingisavailable(38, 39).OtherwiseresistancemaybesuspectediftheHBVviralloadincreasesmorethan1loginacompliantpatienttaking3TC,andthepatientshouldbeswitchedtoTDF(40–42).

• TDFistheessentialARVfortheHAARTregimenin3TC-resistantpatients.


292

4. Monitoring and evaluation of HBV/HIV-coinfected patients

4.1. Hepatitis B treatment responseRelevantresponseisdefinedas:• durablenormalizationofALTlevels;• sustainedHBVDNAsuppression(atleasta1logdecreaseofHBVDNAafterthreemonthsof

treatmentandanundetectableviralload<200IU/mlinthelongterm)(43);• durableHBeAbseroconversionininitiallyHBeAg-positivepatients,veryrarelyobservedwith

nucleotide–nucleosideanaloguesandinHIV-positivepatients.

4.1.1. Monitoring of HBV DNA

SeeTable8.Noteinadditionthefollowing:• InHBeAg-positivepatientswithHBVDNA<20000IU/mlandinHBeAg-negativepatients

withHBVDNA<2000IU/ml,DNAlevelsshouldbemonitoredeverysixmonths.• Inpatientsontreatment(includingARVswithanti-HBVactivity),aninitialresponseisdefined

asatleast1logdropinHBVDNAlevelswithinonetothreemonths.HBVDNAshouldthenbemeasuredatleasteverysixmonthsandifpossibleeverythreemonths.

• ResistanceshouldbesuspectedincompliantpatientsifHBVDNAlevelsincreaseby1logormore.Ifpossible,resistancetestingshouldbeperformed.

Table 8. Monitoring during treatment

Before treatment Month 1 Month 2 Month 3 Every three

monthsEvery six months

EfficacyALT X X X X

HBV DNA X X X(ifavailable) X

4.1.2. Monitoring of ALt

• IftheALTlevelwasinitiallynormal,itshouldbecarefullymonitoredafteronemonth,theneverythreemonthsoverthecourseoftreatment,andeverythreetosixmonthsifnotreatmentisindicated.

• For patients receiving PIs and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs),serumaminotransferaselevelfollow-upiswarrantedeverymonthduringthefirstthreemonthsofstartinganynewART;after this,a follow-upshouldbeperformedevery threemonths toidentifyanydrug-relatedhepatotoxicity.

4.2. Monitoring and evaluation of ARt in HBV/HIV-coinfected patients• CD4cellcountshouldbemonitoredeverythreetosixmonths.• HIVviralload(ifavailable)shouldalsobemonitoredeverysixmonths.

PleaserefertotheProtocol1,Patient evaluation and antiretroviral treatment for adults and ado-lescentsforfurtherinformation.

4.3. Monitoring of adherence to treatment• PatientcounsellingisimportanttoavoiddiscontinuationofHBVdrugregimens.• Patientsshouldbecounselledabouttheside-effectsandtoxicityofHBVandARVdrugsand

advisedtoconsultaphysicianearlyfortoxicitymanagement.• Ifpatientsdonotunderstandthesignsofside-effects,theymaynotreportthemtotheirphysi-

cians,jeopardizingadherence,limitingtreatmentefficacyandincreasingtheriskofdevelopingresistance.


293

FormoreinformationonadherencemonitoringandsupportrefertoProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

4.4. Management of hepatotoxicityAllmedicalstaffshouldbeawareoftheriskofside-effectstoallowthemtomakeearlyrecom-mendationsandinterventions.

Hepatotoxicityisasignificantside-effectofARVusethatmayincreasemorbidityandmortalityamongtreatedHBV/HIV-coinfectedpatients.Themanagementoflivertoxicityisbasedmainlyonitsclinicalimpact,severityandpathogenicmechanism.

4.4.1. Immune reconstitution in HBV/HIV-coinfected patients

TheliverdamageinducedbychronicHBVismainlyimmune-mediated.TheimmunodeficiencycausedbyHIV infection is responsible forattenuating the inflammatory reaction in the liverofHBV/HIV-coinfectedpatients.TheinhibitionofHIVreplicationwithARTleadstothesyndromeofimmunereconstitution,withclinicalhepatitisfollowingthefirstweeksafterinitiationofART,typi-callyinpatientswithverylowCD4countand/orveryhighlevelsofHIVribonucleicacid(RNA)beforeART(44).Thesesymptomsareusuallypreventedbyincludingadual-activitydrugintheARVregimen(seeabove).

4.4.2. Drug-related hepatotoxicity

• Livertoxicitymayalsooccurinpatientsreceivingnucleosideornucleotidereversetranscrip-tase inhibitors (NRTIs), especiallyd4TandddI, andmay lead to severemicrosteatosiswithlacticacidosis(inexceptionalcases).Theconditionispotentiallysevere,withahighmortalityrate,andincaseofsymptomaticlacticacidosisrequiresimmediatelyswitchingtoanotherARVwithadifferenttoxicityprofile.

• Therateofseverehepatotoxicity(grade3or4)associatedwithNNRTIsisrelativelylowbutmaybesignificantlyhigherinHBV-andHCV-coinfectedpatients(45, 46).

• Themajortoxicitiesassociatedwithnevirapine(NVP)arehepatotoxicityandhypersensibilityreactions(rash);bothmaybesevereandlife-threatening.SymptomaticNVP-associatedhepaticorseriousrashtoxicity,althoughuncommon,isthreetoseventimesmorefrequentinwomenthaninmen(47).

• IfCD4>250/mm3,thereisabout10timesgreaterriskofseveresymptomatichepatotoxicitythaninpatientswithCD4<250/mm3.

• TheriskofhepatotoxicityandrasharehighestinthefirstsixweeksofNVPtreatment;startingNVPathalfdosesduringthefirstsixweeksminimizestherisk.

• ElevatedserumaminotransferaselevelsarerelativelycommoninHIV-infectedpatientsreceiv-ingPI-basedART(2–8.5%ofPI-treatedpatients)(48, 49).

• HBV/HIVcoinfectionhasbeenassociatedwithahighriskofdevelopingdrug-inducedliverinjury,andwithagreaterriskofsevereliverinjurythaninpatientswhohaveconcurrentliverdiseasefromothercauses.

• Ifnoothercofactorsexist,thedegreeofhepatotoxicityisthemaindeterminantoftheclinicalapproach.(seeTable9).


294

Table 9. Standardized hepatotoxicity scale (50)

Toxicity grade ALT and AST changes relative to the upper limit of normal Increase from baseline

1 1.25–2.5times 1.25–2.5times2 2.6–5.0times 2.6–3.5times3 5.1–10.0times 3.6–5.0times4 >10.0times >5.0times

• Ifhepatotoxicityissevere,switchingtheARTregimentoonewithlowerpotentialhepatotoxic-ityisrecommended.

• Ifhepatotoxicityismildtomoderate(grades1and2),itisreasonabletocontinuethesameARTregimenwithaclosefollow-upofliverenzymes.

4.4.3. Hepatotoxicity of tB drugs in the context of chronic HBV infection (51, 52)

• TherateofhepatotoxicityissignificantlyhigherinTBpatientswithHCVorHBVcoinfection(59%)thaninthosewithout(24%)(52).

• Commonlyusedanti-TBdrugs,suchasisoniazid,rifampicin,andpyrazinamidarehepatotoxic.• PyrazinamideandisoniazidarethemosthepatotoxicandshouldbeavoidedinTBpatientswith

knownchronicliverdisease.• Itisnotnecessarytoadaptdosageofanti-TBdrugsincasesofhepaticinsufficiency.• Indecompensatedliverdisease,aregimenwithoutrifampicinshouldbeused.• Streptomycin,ethambutolandareservedrugsuchasfluoroquinolonecanbeusediftreatment

isnecessaryinpatientswithfulminantliverdisease.Consultationwithaspecialistisrequired.• Alternativeanti-TBdrugswithlowerhepatotoxicitymaybeusedincaseofliverdysfunction,

for example, rifabutin, amikacin, ofloxacin and levofloxacin.The treatmentof these specialcasesshouldbedecidedinconsultationwithanacknowledgedexpert.

• Hepatotoxicity appears in the first two months ofTB treatment, thus requiring close initialmonitoringofliverfunctions.


295

IV. Suggested minimum data to be collected at the clinical level

Thesuggestedminimumdatatobecollectedareimportantinthedevelopmentofkeyindicatorsonaccesstotreatmentanditssuccess.Suchindicatorsassistmanagersindecision-makingonwaystostrengthenandexpandtheseservicestoallthoseinneed.

Thefollowingdatashouldbecollectedateachclinical facilityonaregularbasis (e.g.monthly,quarterlyorsemi-annually):• numberofHIVpatients(“seenforcare”–thiswillbethedenominatorforthedatabelow);• numberofHIVpatientscoinfectedwithHBV(HbsAg-positive);• numberofHIV-positivepatientswithactivehepatitis;• numberofHIV-positivepatientswithactivehepatitisreceiving: ° HAARTwith3TCand/orTDF; ° ARTwithout3TCand/orTDF; ° exclusivelyonhepatitisBtreatment(e.g.IFNorADF);• numberofHIV-infectedpatientsvaccinatedagainstHBV;and,• numberofHBV/HIVcoinfectedpatientswhohavedied(inagiventimeperiod)includingcause

ofdeath(e.g.liver-relateddeaths,HIV/AIDSrelatedmortalityornon-HIV/AIDSrelatedmor-talitysuchasaccident,overdoseorsuicide).


296

References1. CusterBetal.GlobalepidemiologyofhepatitisBvirus.Journal of Clinical Gastroenterology, 2004,

38(10Suppl):S158–S168.2. Hepatitis B.Geneva,WorldHealthOrganization,WHO,2002(http://www.who.int/csr/disease/hepatitis/

HepatitisB_whocdscsrlyo2002_2.pdf,accessed29March2006).3. Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV

infection?Hepatology, 2004,40(4):790–792.4. ThioC.HepatitisBintheHIV-infectedpatient:epidemiology,naturalhistoryandtreatment.Seminars in

Liver Disease,2003,23:125–136.5. AlterMJ.EpidemiologyofviralhepatitisandHIVcoinfection.Journal of Hepatology,2006,44,Suppl

1:S6–S9.6. KonopnickiDetal.HepatitisBandHIV:prevalence,AIDSprogression,responsetohighlyactiveanti-

retroviraltherapyandincreasedmortalityintheEuroSIDAcohort.AIDS,2005,19(6):593–601.7. NiederauKetal.Long-termfollow-upofHBeAg-positivepatientstreatedwithinterferonalfaforchron-

ichepatitisB.The New England Journal of Medicine, 1996,334:1422–1427.8. ConjeevaramHS,Suk-FongLokA.ManagementofchronichepatitisB. Journal of Hepatology, 2003,

38:S90–S103.9. ThioCLetal.HIV-1,hepatitisBvirus,andriskofliver-relatedmortalityintheMulticenterCohortStudy

(MACS).The Lancet,2002,360(9349):1921–1926.10.PuotiMetal.HepatocellularcarcinomainHIV-infectedpatients:epidemiologicalfeatures,clinicalpre-

sentationandoutcome. AIDS, 2004,18(17):2285–2293.11. LevineOSetal.SeroepidemiologyofhepatitisBvirusinapopulationofinjectingdrugusers;associa-

tionwithdruginjectionpatterns.American Journal of Epidemiology,1995,142(3):331–341.12.PughRNHetal.Preoperativeassessmentofpatientswithliverdisease.British Journal of Surgery,1973,

60:646–649.13.TorbensonM,ThomasDL.OcculthepatitisB.The Lancet Infectious Diseases, 2002,2(8):478–486.14.LokAS,McMahonBJ.ChronichepatitisB.Hepatology,2001,34(6):1225–1241.15.BoninoF,BrunettoMR.ChronichepatitisBeantigen(HBeAg)negative,anti-HBepositivehepatitisB:

anoverview.Journal of Hepatology, 2003,39(Suppl.1):S160–163.16.WildurK,SidhurK.Betablockerprophylaxisforpatientswithvaricealhaemorrhage. Journal of Clinical

Gastroenterology, 2005,39(5):435–440.17.BedossaP,PoynardT,METAVIRComparativeGroup.Inte-andintra-observervariationintheassess-

mentofliverbiopsyofchronichepatitisC. Hepatology, 1994,20:15–20.18.Simmondsetal.Epidemiological,clinicalandtherapeuticassociationsofhepatitisCtypesinwestern

Europeanpatients.Journal of Hepatology,1996,24(5):517-524.19.MyersRetal.Predictionofliverhistologicallesionswithbiochemicalmarkersinpatientswithchronic

hepatitisB. Journal of Hepatology,2003,39:222–230.20.SandrinLetal.Transientelastography:anewnon-invasivemethodforassessmentofhepaticfibrosis.

Ultrasound in Medicine & Biology,2003,29:1705–1713.21.DeLédinghenVetal.DiagnosisofhepaticfibrosisandcirrhosisbytransientelastographyinHIV/hepa-

titisCvirus-coinfectedpatients.Journal of Acquired Immune Deficiency Syndrome,2006,41(2).22.Nunes D et al. HIV infection does not affect the performance of non-invasive markers of

fibrosisforthediagnosisofhepatitisCvirus-relatedliverdisease.Journal of Acquired Immune Defi-ciency Syndrome, 2005,40(5).

23.HassanMMetal.Riskfactorsforhepatocellularcarcinoma:synergismofalcoholwithviralhepatitisanddiabetesmellitus.Hepatology,2002,36:1206–1213.

24.LucasGMetal.LongitudinalassessmentoftheeffectsofdrugandalcoholabuseonHIV-1outcomestreatmentinanurbanclinic.AIDS,2002,16:767–774.

25.FerenciP,FormannE,RomeoR.SuccessfultreatmentofchronichepatitisDwithashortcourseofpe-ginterferonalfa-2a.American Journal of Gastroenterology,2005,100(7):1626–1627.

26.CooksleyW.Treatmentwithinterferons(includingpegylatedinterferons)inpatientswithchronichepa-titisB.Seminars in Liver Disease, 2004,24(Suppl.1):45–53.

27.SHadziyannisetal.Long-termadefovirdipivoxiltreatmentinducesregressionofliverfibrosisinpa-tientswithHBeAg-negativechronichepatitisB:resultsafter5yearsoftherapy.American Association


297

for the Study of Liver Diseases, 11–15 November, 2005, San Francisco, California. (PosterNumberLB14).

28.MarcellinPetal.AdefovirdipivoxilforthetreatmentofhepatitisBeantigen-positivechronichepatitisB.The New England Journal of Medicine, 2003,348:808–816.

29.SorianoVetal.CareofpatientswithchronichepatitisBandHIVcoinfection:recommendationsfromanHIV-HBVinternationalpanel.AIDS,2005,19(3):221–240.

30.Bani-Sadr F et al. Ninety-six week efficacy of combination therapy with lamivudine andtenofovirinpatientscoinfectedwithHIV-1andwildtypehepatitisBvirus.Clinical Infectious Diseases,2004,39:1062–1064.

31.Dore G et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive andexperiencedpatientscoinfectedwithHIV-1andhepatitisBvirus.Journal of Infectious Diseases, 2004,189:1185–1192.

32.NelsonM,PortsmouthS,StebbingJ.Anopen-labelstudyoftenofovirinHIV-1andhepatitisBviruscoinfectedindividuals.AIDS, 2003,17:F7–F10.

33.GishRet al.Dose range studyofpharmacokinetics, safety andpreliminaryantiviral activityof em-tricitabine in adultswith hepatitisB virus infection. Antimicrobial Agents and Chemotherapy, 2002,46:1734–1740.

34.BangL,ScottL.Emtricitabine.Drugs, 2003,63:2413–2424.35.AllavenaCetal.Efficacyandtolerabilityofanucleosidereversetranscriptaseinhibitor–sparingcom-

binationof lopinavir/ritonavir andefavirenz inHIV-1 infectedpatients. Journal of Acquired Immune Deficiency Syndrome, 2005,39(3):300–306.

36.BessesenMetal.ChronicactivehepatitisBexacerbationsinHIV-infectedpatientsfollowingdevelop-mentofresistancetoorwithdrawaloflamivudine.Clinical Infectious Diseases,1999,28:1032–1035.

37.BenhamouYetal.Long-termincidenceofhepatitisBvirusresistancetolamivudineinHIV-infectedpatients.Hepatology,1999,30:1302–1306.

38.LiawYF.ImpactofYMDDmutationsduringlamivudinetherapyinpatientswithchronichepatitisB.Antimicrobial Agents and Chemotherapy, 2001,12Suppl1:67–71.

39.LiawYF.ManagementofYMDDmutationsduringlamivudinetherapyinpatientswithchronichepatitisB. Journal of Gastroenterology and Hepatology, 2002,17Suppl3:S333–S337.

40.LadaOetal.Invitrosusceptibilityoflamivudine-resistanthepatitisBvirustoadefovirandtenofovir.Antiviral Therapy, 2004,9:353–363.

41.NúñezMetal.ActivityoftenofovironhepatitisBvirusreplicationinHIV-coinfectedpatientsfailingorpartiallyrespondingtolamivudine. AIDS, 2002,16:2352–2354.

42.SchildgenOetal.SuccessfultherapyofhepatitisBwithtenofovirinHIV-infectedpatientsfailingprevi-ousadefovirandlamivudinetreatment.AIDS,2004,18(17):2325–2327.

43.Mommeja-MarinHetal.SerumHBV-DNAasamarkerofefficacyduringtherapyforchronichepatitisBinfection:analysisandreviewoftheliterature. Hepatology, 2003,37:1309–1319.

44.Drake A, Mijch A, Sasadeusz J. Immune reconstitution hepatitis in HIV and hepatitis B coin-fection, despite lamivudine therapy as part of HAART. Clinical Infectious Diseases, 2004, 39:129–132.

45.DieterichDTetal.Drug-inducedliverinjuryassociatedwiththeuseofnon-nucleosidereverse-transcrip-taseinhibitors.Clinical Infectious Diseases, 2004,38Suppl2:S80–S89.

46.MartínezEetal.HepatotoxicityinHIV-infectedpatientsreceivingnevirapine-containingantiretroviraltherapy.AIDS 2001,15:1261–1268.

47.SulkowskiMS et al.Hepatotoxicity associatedwith nevirapine or efavirenz-containing antiretroviraltherapy:roleofhepatitisCandBinfections.Hepatology,2002,35(1):182–189.

48.SulkowskiMS.HepatotoxicityassociatedwithantiretroviraltherapycontainingHIV-1proteaseinhibi-tors.Seminars in Liver Disease, 2003,23(2):183–194.

49.SulkowskiMSetal.HepatotoxicityassociatedwithantiretroviraltherapyinadultsinfectedwithhumanimmunodeficiencyvirusandtheroleofhepatitisCorBvirusinfection.JAMA,2000,283(1):74–80.

50.PolS,LebrayP,Vallet-PichardA.HIVinfectionandhepaticenzymeabnormalities:intricaciesofthepathogenicmechanisms.Clinical Infectious Diseases,2004,38Suppl2:S65–S72.

51.AaronLetal.TuberculosisinHIV-infectedpatients:acomprehensivereview.Clinical Microbiology and Infection,2004,10(5):388–398.

52.PanLetal.Effectofanti-tuberculosistherapyonliverfunctionofpulmonarytuberculosispatientsin-fectedwithhepatitisBvirus.World Journal of Gastroenterology, 2005,11(16):2518–2521.

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