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
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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).
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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.
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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
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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
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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.)
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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.
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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.
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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).
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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.
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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).
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