4 Management of Tuberculosis and HIV Coinfection

Contents

I. Epidemiology of TB, TB/HIV/AIDS and reciprocal influence of TB and HIV................... 135 1.EpidemiologyofTB.............................................................................................................. 135 2.EpidemiologyofTB/HIVcoinfection................................................................................... 135 3.ReciprocalinfluenceofHIVandTB..................................................................................... 136 3.1.InfluenceofHIVonthedevelopmentofactiveTB....................................................... 136 3.2.InfluenceofHIVonthetransmissionofTB.................................................................. 136 3.3.InfluenceofHIVontheclinicalpresentationofTB...................................................... 136 3.4.InfluenceofTBonHIVmorbidityandmortality.......................................................... 136

II. Identification of TB/HIV in adults and adolescents............................................................. 137 1.TBriskassessmentanddiagnosisinPLHIV........................................................................ 137 2.HIVriskassessmentanddiagnosisinpatientswithTB....................................................... 137

III. Clinical management of TB/HIV in adults and adolescents.............................................. 139 1.Managementofcoinfectedpatients...................................................................................... 139 2.ManagementofcoinfectedpatientswithactiveTB.............................................................. 139 2.1.TBtreatment.................................................................................................................. 139 2.2.Initiationofantiretroviraltreatment............................................................................... 140 2.3.First-lineHAARTregimens........................................................................................... 141 2.3.1.Keyconsiderationsforfirst-lineregimens........................................................... 141 2.3.2.Treatmentfailure.................................................................................................. 141 2.4.Second-lineHAARTregimens...................................................................................... 142 2.4.1.Keyconsiderationsforsecond-lineregimens...................................................... 142 2.5.ARVandTBdruginteractionsandmanagement........................................................... 142 2.6.Cotrimoxazoleprimaryprophylaxis.............................................................................. 143 3.ClinicalmanagementofTB/HIVinspecialconditions........................................................ 143 3.1.Renalfailure................................................................................................................... 143 3.2.Liverdisease.................................................................................................................. 143 3.3.Womenofchildbearingage........................................................................................... 144 3.4.Pregnantwomen............................................................................................................. 144 3.5.Injectingdrugusers........................................................................................................ 144 4.MonitoringTB/HIV-coinfectedpatients............................................................................... 145 4.1.MonitoringTBtreatment............................................................................................... 145 4.2.Monitoringantiretroviraltreatment............................................................................... 145 4.3.AdherencetoTBtreatmentandARVtreatment............................................................ 146

IV. Identification of TB/HIV in infants and children................................................................ 148 1.IdentificationofTBinHIV-infectedinfantsandchildren.................................................... 148 2.IdentificationofHIVinchildrenwithactiveTB.................................................................. 149

V. Clinical management of TB/HIV in children........................................................................ 150 1.TreatmentofTB.................................................................................................................... 150 2.TreatmentofHIV/AIDS........................................................................................................ 150 2.1.InitiationofART............................................................................................................ 150 2.2.RecommendedHAARTregiments................................................................................ 151 2.3.KeyconsiderationsforARVdrugs................................................................................ 151 2.4.Cotrimoxazoleprimaryprophylaxis.............................................................................. 151 3.MonitoringofTB/HIV-coinfectedchildren.......................................................................... 151

VI. Suggested minimum data to be collected at the clinical level............................................ 152

Annex 1. TB drugs (adults, adolescents and children)............................................................. 153

Annex 2. ARV drugs (adults and adolescents).......................................................................... 154

References..................................................................................................................................... 156

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ManageMent of tuberculosis and HiV coinfection

I. Epidemiology of TB, TB/HIV/AIDS and reciprocal influence of TB and HIV

1. Epidemiology of TBTuberculosis(TB)isaseriouspublichealthproblemintheWHOEuropeanRegion,whereaccord-ingtothemostrecentWHOestimates,almost445000newcasesandmorethan69000relateddeathsoccurredin2004.TheoverallTBincidenceratefortheRegionis50per100000popula-tion,rangingnationallyfrom2/100000inMonacoto177/100000inTajikistan.Bysubregion,theratesare12/100000forwesternEurope,27/100000forcentralEuropeand96/100000foreasternEurope.Amongthe22high-burdenTBcountriesintheworld,theRussianFederationranks12th(1, 2).

Asnoted,thehighestratesofTBarereportedinthecountriesofeasternEurope,whereweakenedeconomiesandpublichealtheffortsarethemaincausesofitsresurgence,andwhereinternation-allyrecommendedcontrolstrategiesneedfurtherexpansionandstrengthening.InwesternEurope,therearepocketsof increasing incidence,particularly inmajorcitieswithsociallymarginalizedimmigrantsfromhigh-burdenTBcountries(3, 4).

TheEuropeanRegion has the highest prevalence rates in theworld formultidrug-resistantTB(MDR-TB);itincludessevenoftheninecountriesintheworldwith>6.5%prevalenceofMDR-TBinnewcases(Estonia,Israel,Kazakhstan,Latvia,Lithuania,theRussianFederationandUz-bekistan),aswellasfiveoftheninecountrieswith>30%prevalenceofMDR-TBinpreviouslytreatedcases(Estonia,Kazakhstan,Lithuania,theRussianFederationandUzbekistan)(5).

TBismorefrequentlyfoundamongprisonersthanintheoutsidepopulation.TheaverageprisonpopulationrateintheEuropeanRegionisabout100prisonersper100000inhabitants,withhigherratesintheeasternpartoftheRegion.IntheRussianFederation,the2003ratewasapproximately600/100000(6).In2003,morethan7%ofthenewTBcasesreportedtoWHORegionalOfficeforEuropeweredetectedinprisons,withlargevariationsamongcountries(range0.1–30.4%)(7–10).

2. Epidemiology of TB/HIV coinfectionIneasternEuropethereareindependentepidemicsofTBandHIV/AIDS,andalargemajorityofTBpatientsdevelopedtheirdiseasewithoutHIV-relatedimmunosuppression.AmongpeoplelivingwithHIV(PLHIV),theriskofacquiringTBishigherwheretheTBprevalenceishigh.In2004,westernandeasternEuropeancountriesreportedTBasthemostfrequentAIDS-indicativedisease,withrespectiveratesof24%and56%ofnewlyreportedAIDScases(11, 12).Unfortunately,knowl-edgeoftherealextentofTB/HIVcoinfectioninEuropeislimitedduetoinsufficientsurveillancedata.AstheresultoftherecentdramaticincreaseofHIVprevalenceineasternEurope,aswellasthehighprevalenceofTBthere,itisexpectedthatthenumberofTB/HIVpatientswilldramaticallyincreaseinthenextfewyears(12–14).

PrisonersaremorevulnerabletobecominginfectedwithTBandHIVduetoenvironmentalandnu-tritionalfactorsthatincreasetheirexposure,vulnerabilityandrisk-takingbehaviour.Prisons,withtheiroftencrowdedandenclosedconditions,poorventilation,inadequatelightingandcontinuousexposuretoTB-infectedpeople,facilitateairborneTBtransmission.Malnutritionalsocontributestothehigherriskforprisontransmission.Inaddition,commonprisonbehaviours–unsafeinject-ingdrugpractices,tattooingandunprotectedsex–exposeprisonerstoHIVinfection,aswellashepatitisBandC(15).

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HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION

3. Reciprocal influence of HIV and TB

3.1. Influence of HIV on the development of active TBHIVpromotestheprogressionofinfectionwithMycobacteriumtuberculosistoactiveTB,bothinpeoplewithrecentlyacquiredinfectionsandthosewithlatentinfections.Undeniably,HIVisthemostpowerfulriskfactorknownforactivationoflatentM.tuberculosisinfection.ForanHIV-in-fectedperson-coinfectedwithM.tuberculosis,theriskofdevelopingactiveTBreaches5–10%an-nually,insteadofthe5–10%lifetimeriskforanindividualnotinfectedwithHIV.ThisdiscrepancyisclearlylinkedtotheimmunodeficiencycausedbyHIV.Furthermore,HIVinfectionincreasestherateofrecurrentTB,whichcanbeduetoeitherendogenousreactivationorexogenousreinfection(16, 17).

3.2. Influence of HIV on the transmission of TBTBisoneofthemostcommoninfectionsinHIV-infectedpeople,especiallyinhighTBprevalenceareas.HIVgreatlyincreasesthenumberofTBpatients,whichinturnincreasesTBtransmissionfromfamilymembers(thehighestTBtransmissionriskisfromhouseholdcontacts,suchaschil-drenandHIV-positivepartners)andcommunitymembers(throughcontactinwork-places,schoolsandhospitals)wherethereisariskofnosocomialinfectionsfrombothpatients(whetherHIV-posi-tiveor-negative)andhealthcareworkers.Moreover, theriskofMDR-TBtransmissionmaybeincreasedifeffectiveanduninterruptedTBtreatmentisnotensured(18–20).

3.3. Influence of HIV on the clinical presentation of TBAsHIVinfectionprogresses,CD4lymphocytesdeclinebyabout50–80cells/mm3/year,andtheim-munesystembecomeslessabletopreventthegrowthandlocalspreadofM. tuberculosis.

PulmonaryTB(PTB)remains,especiallyinadults,thecommonestformofTB,butitspresentationdependsonthedegreeofimmunosuppression.Theclinicalpictures,sputum-smearresultsandchestX-raysareoftendifferentintheearlystageofHIVinfection(CD4>350cells/mm3)andthelatestage(CD4<200cells/mm3).TheclinicalpresentationofTBcasesinearlyHIVinfectionissimilartothatofindividualswithoutHIVinfection,resemblingpost-primaryPTB,thatis,withpositivesputumsmears(definedastwoormoreinitialsmearexaminationsthatarepositiveforacid-fastbacilli(AFB),oroneplusconsistentradiographicabnormalities)andoftenwithcavitiesinthechestX-ray.Incontrast,theclinicalpresentationinlateHIVcasesresemblesprimaryPTB:thesputumsmearisoftennegativeandradiologicalinfiltratesarepresentinsteadofcavities(21–23).Incaseofsevereimmunodeficiency,therateofextrapulmonaryTB(EPTB)increasesinbothadultsandchildren.Becauseofdifficultiesindiagnosis,disseminatedTBmayaccountforahighproportionofmisattributedhospitaldeaths.

3.4. Influence of TB on HIV morbidity and mortalityActiveTBitselfisresponsibleforamildimmunedeficiency.Incountrieswithindependentepidem-icsofTBandHIV/AIDS,TBdoesnotalwaysindicateseveredeteriorationoftheimmunesysteminHIV-infectedpeoplebecauseitmayoccurbeforeHIVinfectionorinitsearlystages,beforetheim-munesystemhasdeteriorated.WhenactiveTBoccursinHIVpatients,aworseningoftheHIV-re-lateddeficiencyiscommonlyobserved,facilitatingtheprogressionofotheropportunisticinfectionssuchasCandidaalbicansoesophagitis,Cryptococcusmeningitisand,particularly,Pneumocystisjirovecii(formerlyP. carinii)pneumonia.Anyoftheseopportunisticinfectionsmaybelethal.Ifso,TBisindirectlyresponsibleforthedeath(24).

Inaddition,TBhasbeenfounddirectlyresponsibleforanaveragemortalityrateof30%amongHIV/AIDScasesinmanyreports(22, 23, 25).ThesedataemphasizetheneedofearlydiagnosisandspecifictreatmentofTBinallHIV-infectedpatients,especiallywhentheclinicalpatternofCD4cellscountshowsaseveredegreeofimmunodeficiency.

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II. Identification of TB/HIV in adults and adolescents

AllHIV-positivepeopleshouldbeassessedforriskfactorsforhavingoracquiringTB,justasallpatientswithactiveTBdiseaseshouldbeofferedHIVtestingandcounselling.Themajorreasonsforthisare:• HIV-positivepeopleareathigherriskforhavingordevelopingactiveTB,oneofthemajorop-

portunisticinfectionscausingdeathinPLHIV;• HIVinfectioninfluencestheclinicalprogressionofTBanditstreatment;• TBdiseaseinfluencestheclinicalprogressionofHIV/AIDSanditstreatment;and• TBmaybeanindicativesignofadvancedHIV/AIDSdisease.

1. TB risk assessment and diagnosis in PLHIVInassessingPLHIVforTBrisk,particularattentionshouldbepaidto:• peoplewithrespiratorysymptoms;• householdcontactsofanyonewithanactivecaseofpulmonaryTB;and• coexistingriskfactorsandvulnerability-increasingfactors(e.g.injectingdruguse,alcoholabuse

andincarceration).

TheinitialassessmentforTBshouldinclude:• ahistoryofTBexposure(individualandhousehold);and• ahistoryofpossiblyrelatedsymptoms(especiallyacoughofmore thantwoweeksduration

withoutanyclearexplanation).

IfanHIV-infectedpersondoesnothaveanobviousriskforTB(recentexposureorclinicalsymp-toms),atuberculinskintest1shouldbeperformedtoidentifythestatusofanylatentTBinfectionthatmayevolveintoTBdiseaseduetoHIV-relatedimmunosuppression.(SeeFig.1below.)

ApositivetuberculinskintestisindicativeofpastorrecentTBinfection,whichisaconditionforstartingTBpreventivetreatment(TPT).AnegativetuberculinskintestinPLHIVusuallymeansnoriskofTB(exceptinthosewithsevereimmunosuppression).

IfanHIV-infectedpersonhasbeenrecentlyexposedtoTBorhasclinicalsymptomsindicativeofpulmonaryorextrapulmonaryTBdisease,thestatusofactiveTBdiseaseshouldbeexplored.Ac-tiveTBcanbeexcludedthroughcarefulclinicalexamination,bacteriologicalinvestigation(sputummicroscopyandculture)andX-ray.IncaseofinfiltrateinthechestX-ray,aclinicaltrialwithafullcourseofbroad-spectrumantibioticsmaybenecessarytomakeadiagnosisdifferentiatingbetweenTBandnonspecificpneumonia.WhenactiveTBdiseaseisexcluded,thepossibilityoflatentTBinfectionshouldbeexploredthroughatuberculinskintest.

IfanHIV-infectedpersonhasactiveTBdisease,heorsheshouldbetreatedasdescribedinsectionIIIbelow.

1Tuberculinisapurifiedproteinderivedfromtuberclebacilli.TuberculininjectedintotheskinofaTB-infectedpersonpro-ducesadelayedlocalreactionafter24to48hours,whichisquantifiedbymeasuringthediameteroftherelatedskininduration(thickening).ThetestisusuallyconsideredpositiveinHIV-infectedpeoplewhenindurationexceeds5mm.ThereactiononlyshowsthatthepersonhasatsometimebeeninfectedwithM. tuberculosis (15, 17).

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Fig. 1. algorithm for assessing tb risk and disease in an HiV-positive person

RecentTBexposureorTBsymptoms

Yes No

ExclusionorconfirmationofactiveTB(clinicalexamination,sputum-smearmicroscopy,X-ray,

trialwithabroad-spectrumantibiotic)

ActiveTB ActiveTBexcluded

TBtreatmentTuberculinskintest

Positive Negative

TBpreventivetreatment

2. HIV risk assessment and diagnosis in patients with TBOfferingHIVtestingandcounsellingshouldbearoutineprocedureinhealthcaresettingsdealingwithpatientswhohaveactiveTB.Healthcareprovidersshouldexplaintothepatientsthereasonsforoffering the testand the importanceofknowing theresults forcorrectclinicalmanagement.However,allpatientshavetherighttorefuseanHIVtest.Theinitialassessmentofapatient’sHIVstatusshouldinclude:• HIVpretestcounselling;• serologicaltests(typically,ELISAand/orrapidtests)forHIVantibodies,followedbyawestern

blotconfirmatorytest;and• post-testcounselling,includinginformationonreducingriskybehaviour,irrespectiveofthere-

sultsoftheHIVtest.

FurtherevaluationofpatientsfoundtobeHIV-infectedisrequiredtodecideonaclinicalmanage-mentstrategy.Formoredetailedinformation,seeProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

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III. Clinical management of TB/HIV in adults and adolescents

For clinicalmanagement ofTB/HIV-coinfected patients, amajor consideration iswhen to starttreatment.

AfterinitialassessmentofTBandHIVstatus,apatientwithTB/HIVwouldfitinoneoftwoTBcategories,eachrequiringadifferentclinicalmanagementstrategy,andeachofwhichmayormaynotrequireART:1. TB-infection(positivetuberculinskintest)2. activeTBdisease.

1. Management of coinfected patientsHIV-infectedpatientscoinfectedwithTBhaveahigherriskofdevelopingactiveTB;therefore,tuberculosispreventivetreatment(TPT)shouldbeinitiatedwithisoniazid5mg/kg(300mgmaxi-mum)oncedaily(OD)forsixmonths.

Alternativescheduleshavebeensuggestedtoimproveadherence,butfurtherresearchisneededtoprovetheirefficacy.FurtherresearchisalsoneededfordevelopingalternativeTPTinareaswithhighprevalenceofisoniazidresistance(26–28).Theadditionof6mgpyridoxinedailycanpreventperipheralneuropathy,especiallyinpregnantwomen,alcoholicsandthemalnourished.

ThedecisionofwhentostartARTisbasedonanumberofindicators,ofwhichthemostimportantaretheHIV/AIDSclinicalstageandimmunologicalcriteria(pleaserefertothesectiononInitia-tionofHAARTandWHOClinicalstagingofHIV/AIDSforadultsandadolescents,inProtocol 1,Patient evaluation and antiretroviral treatment for adults and adolescents).

TPTcanalsobegivensimultaneouslywithART.MoreevidenceisrequiredtoidentifythethresholdofCD4countabovewhichTPTcanbeconsideredlessnecessary.

2. Management of coinfected patients with active TB

2.1. TB treatmentTBtreatmentinHIV-infectedpatientsisapriorityandshouldbestartedassoonasactiveTBhasbeendiagnosed.TreatingTBpromptlywillreduceTB-relatedmortalityandtheriskoftransmission(15, 29, 30).

TreatmentofTB,regardlessofitsconcomitancewithART,shouldbebasedondrugsofknownbio-availability.TBtreatmentregimensconsistoftwophases:aninitialphaseandacontinuationphase.EachTBdrughasanabbreviation(ethambutol:E,isoniazid:H,pyrazinamide:Z,rifampicin:R,streptomycin:S);forfurtherinformationondrugdosagesseeAnnex1.Thedurationoftheinitialphaseis2–3months,thecontinuationphase,4–5months.PresentevidenceclearlyshowsthatTBrelapseinHIV-infectedpatientsisminimizedbyaregimencontainingrifampicinthroughoutthecourseoftreatment.

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Table 1. recommended tb treatment regimens for PlHiV with active tb

Type of TB caseTB.treatment.regimena

Initial phaseb Continuation phase

NewTBpatient HRZE2monthsc HR4months

PreviouslyTB-treatedpatient,including:• relapse• treatmentafterdefault• treatmentfailured

HRZES2monthsorHRZE1month HRE5months

ChronicorMDR-TBcases(stillsputum-positiveaftersupervisedre-treatment)

Aspeciallydesignedregimen,whetherstandardoradhoc

E:ethambutol;H:isoniazid;R:rifampicin;S:streptomycin;Z:pyrazinamide.aDailyTBtreatmentisrecommendedforHIV-positivepatientswithactiveTB.bDirectobservationofdrugintakeisrecommendedduringtheentirecourseoftherapy,particularlyintheinitialphase.cStreptomycinmaybeusedinsteadofethambutol.InmeningealTB,ethambutolshouldbereplacedbystreptomycin,whichdiffusesmoreinthemeninges.dWheneverpossible,drugsensitivitytestingshouldbedonetoenableanindividualizedtreatmentregimen.

2.2. Initiation of antiretroviral treatmentManypatientswithactiveTBhaveadvancedHIVdiseaseandarethereforeeligibleforART,whichshouldnotbewithheldsimplybecauseapatientisreceivingorisabouttoreceiveTBtreatment.Nevertheless,it ispreferablenottoinitiatetreatmentforHIVandTBsimultaneously,andwhenpossibletodelayART(seeTable2)(31–34).Thisstrategy:• simplifiespatientmanagement• avoidsantiretroviral(ARV)andTBdruginteractions• avoidsoverlappingtoxicities• limitsriskofimmunereconstitutioninflammatorysyndrome(IRIS)• minimizesconfusionaboutwhatdrugstotakewhen,andforwhichdisease• increasesadherence.

Table 2. strategy for initiation of treatment for both tb and HiV infection

Criteria TB.treatment ART

ExtrapulmonaryTB(regardlessofCD4count) Startimmediately StartARTassoonasTBtreatment

istolerated(betweentwoweeksandtwomonths)a.PulmonaryTB

CD4<200cells/mm3 Startimmediately

PulmonaryTBCD4=200–350cells/mm3 Startimmediately

StartARTaftercompletionofinitialTBtreatmentphase(startearlierifseverelycompromised).

PulmonaryTBCD4>350cells/mm3 Startimmediately

MonitorCD4count.ConsiderARTifCD4cellcountdropsbelow350cells/mm3.

aThedecisiontostartARTshouldalsobebasedonclinicalevaluationofothersignsofimmunodeficiency.

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2.3. First-line HAART regimens Highly active antiretroviral treatment (HAART) is the standard recommendedART. It includesthreeorinsomecasesmoreARVdrugs.ThemainfactorstoconsiderinselectingthebestARVregimensforTBpatientsare:• potency• sideeffectsandtoxicity• simplicity,toallowbetteradherence.

ARTduringTBtreatmentrequiresgivingspecialconsiderationto:• interactionsbetweenrifampicinandsomeARVs• pillburden• theimportanceofhighadherence• drugtoxicity• theriskofimmunereconstitutionsyndrome.

Table 3. recommended first-line Haart for patients being treated for tb with rifam-picina

ARV drug classes HAART regimes

Preferred 2NRTIs+1NNRTI ZDV(orTDF)+3TC(orFTC)+EFVb

Alternative 3NRTIs(triple-nukeregimen) ZDV+3TC+ABC(orTDF)

aSeeAnnex2fordosagesbRecommendedefavirenz(EFV)doseis600mg/dayespeciallyinpatientswith<60kgbodyweight(35–37).Increasingthedoseto800mg/daycanbeconsideredinpatientswith>60kgbodyweight,thoughfurtherresearchisneeded.IfEFVisnotavailable,Nevirapine(NVP)canbeused[200mgODfor2weeksfollowedby200mgtwicedaily(BID)]withclosemonitor-ingofliverfunctionanddrugtoxicity.[ZDV+3TC+NVPisavailableinanfixed-dosecombination(FDC).]

2.3.1. Key considerations for first-line regimens

ZDV (or TDF) + 3TC (or FTC) + EFV (seeTable3)• Norifampicindoseadjustmentisrequired• EFVdecreasesmethadonelevelssignificantly;thisisimportanttorememberfortreatmentofinjectingdrugusers(IDU)onopioidsubstitutiontherapy.ForfurtherinformationpleaserefertoProtocol5,HIV/AIDS treatment and care for injecting drug users.

ZDV + 3TC + ABC (or TDF) (seeTable3)• Norifampicindoseadjustmentisrequired.• PregnantwomenwithTBcansafelyuseZDV+3TC+ABC.

Foradditionalconsiderationsregardingfirst-lineARTregimens,pleaserefertoProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

2.3.2. Treatment failure

ResponsetoARTismonitoredbyclinicalsymptoms,CD4countandviralload.Forfurtherinfor-mationontreatmentfailurecriteriapleaserefertoProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

TBisnotacriterionfortreatmentfailureinitselfandifitoccurswithoutotherevidenceofimmu-nodeficiencyinpatientsonafirst-lineregimen,theyshouldnotbeswitchedtoasecond-lineregi-men.Ifapatientonasecond-lineARTdevelopsTBduringtreatment,theproteaseinhibitor(PI)componentneedstobeadjusted.

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2.4. Second-line HAART regimens

Table 4. recommended second-line Haart for patients receiving tb treatment with rifampicin

ARV drug classes HAART regimens

Preferred 2NRTIs+2PIs(oneofthemboosted)

ABC+ddI+LPV/r+RTVor

TDF+ddI+LPV/r+RTV

Alternative 2NRTIs+2PIsABC+ddI+SQV+RTV

orTDF+ddI+SQV+RTV

2.4.1. Key considerations for second-line regimens

ABC (or TDF) + ddI + LPV/r + RTV (seeTable4)• IfddIisadministeredwithTDF,itsdosageshouldbeadjustedduetotoxicpancreaticandnega-

tiveimmuneeffects.TherecommendeddoseofddIwhenadministeredwithTDF(300mgOD)is: ° 250mgODforpatientswith>60kgbodyweight ° 125–200mgODforpatientswith<60kgbodyweight(38, 39).• WhenLPV/r400/100mgBIDisadministered,RTV300mgBIDshouldbeadded,withclose

monitoringofliverfunctionsandlipidlevels.

ABC (or TDF) + ddI + SQV + RTV (seeTable4)• WhenSQVisadministered,therecommendeddailydosagesofSQVandRTVareeach400mg,

andclosemonitoringofliverfunctionsisrequired.• Norifampicindosageadjustmentisrequiredwiththeseregimens.

2.5. ARV and TB drug interactions and management• RifampicinstimulatestheactivityofthehepaticcytochromeP450(CYP)enzymesystemthat

metabolizesNNRTIsandPIs(seeAnnex2forARVclasses).Thismechanismleadstoareduc-tioninthebloodlevelsofNNRTIsandPIs,andconsequentlytheincompletesuppressionofHIVreplicationandtheemergenceofdrugresistance.Rifampicincausesuptoa75%reductionintheserumlevelsofPIs,thusnecessitatingdosageadjustment.

• NNRTIsandPIscanalsoenhanceorinhibitCYPandleadtoalteredbloodlevelsofrifampicin.Therefore,whenrifampicinisusedconcomitantlywithNNRTIsandPIs,adailyregimenispre-ferred(40–42).

• TheeffectsofrifampicinandNNRTIsandPIsontheCYParebothcomplexandcommon,butunlessadefinitivecontraindicationexists,rifampicinisthepreferredTBdrug.ThereasonisthattherateofTBrelapseinHIV-positivepatientsbecomesaslowasinHIV-negativepatientswhentreatedfor≥6monthswithrifampicin-containingregimens.

• Rifampicinhasnoeffectontheserumlevelsofnucleosidereversetranscriptaseinhibitors(whicharenotmetabolizedbyCYP),andnodosageadjustmentofthesedrugsisnecessary.

• Inpatientsonsecond-lineART,rifabutin150mgeveryotherday(QOD)or3times/weekcanbeusedsafelyasanalternativetorifampicin.RifabutinmaybepreferredinsettingswithalimitedcapacitytoadjustPIdosage;however,itismoreexpensivethanrifampicin.

• RifabutinshouldnotbeprescribedwithunboostedSQV,butitcanbeusedwithcombinationofSQVwithRTV.

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2.6. Cotrimoxazole primary prophylaxis TB/HIV-coinfectedpatientsmaydiesoonafterthecommencementoftreatmentifitisstartedattooadvancedanHIV/AIDSstage.DeathmayberelatedtotheprogressionofTBitself,butinmanycases thedeath is related to theprogressionof other opportunistic infections, such asPneumo-cystis jiroveciipneumonia(PCP)orToxoplasma gondiiencephalitis(TE)(32).Therefore,primaryprophylaxiswithcotrimoxazole(trimethoprim-sulfamethoxazole)isneededasprophylaxisagainstPCPandTE.• PatientswithaCD4count<200cells/mm3orwhoareatClinicalStage3(withoropharyngeal

candidiasis,forexample)orClinicalStage4shouldreceivecotrimoxazolesimultaneouslywithTBtreatment(ifindicated)untiltheCD4cellcounthasstabilizedfor4–6months,oratleast3monthsat>200cells/mm3.

• The recommended prophylaxis with cotrimoxazole in adults is one double-strength tablet:160/800mgOD.

• Adherencetocotrimoxazoleiscritical,anddirectobservationofitsadministration,togetherwiththeadministrationofTBdrugs,maybeuseful,particularlyinveryillpatients.

Formoreinformation,pleaserefertoProtocol2,Management of opportunistic infections and gen-eral symptoms of HIV/AIDS,sectiononOIprophylaxisinHIVinfectedpatients.

3. Clinical management of TB/HIV in special conditions

3.1. Renal failure• Isoniazid,rifampicinandpyrazinamideareeithereliminatedalmostentirelybybiliaryexcretion

ormetabolizedintonon-toxiccompounds.Thesedrugscanthereforebegiveninnormaldosagetopatientswithrenalfailure.

• Patientswithsevererenalfailureshouldreceivepyridoxinewithisoniazidinordertopreventperipheralneuropathy.

• Streptomycinandethambutol,however,areexcretedby thekidney.Theyshouldbegiven inreduceddoses,andrenalfunctionshouldbemonitoredclosely(creatininelevelmonthly).

• TDFshouldbeavoidedinARVregimensduetoitsknownnephrotoxicity.

Table 5. recommended tb regimens for patients with renal failurea

Initial phase Continuation phase

Preferential HRZ2months HR4months

Alternative(ifmonitoringofrenalfunctionispossible)

HRZE2months HR4months

aRenalfailureisdefinedasoccurringwhenthecreatininelevelincreasesto130–160micromoles/litre.

3.2. Liver disease• Isoniazid,rifampicinandpyrazinamideareallassociatedwithdrug-inducedhepatitis.• Pyrazinamideisthemosthepatotoxic,followedbyrifampicin.Rifampicinislesslikelytocause

hepatocellulardamage,althoughitisassociatedwithcholestaticjaundice.• Patientswithliverdiseaseshouldnotreceivepyrazinamide.AlternativeTBtreatmentregimens

arelistedinTable6.• Clinicalmonitoringoftheliverandlaboratorymonitoringofliverenzymesshouldbeperformed

todetectanyexacerbationofthecondition.Theyshouldbedoneonaregularbasis,atafre-quencythatdependsonthepatient’scondition.

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Table 6. recommended tb regimens for patients with liver diseasea

Initial phase Continuation phase

Preferential SHRE2months HR6months

1st Alternative SHE2months HE10months

2nd Alternative RE9months –aLiverdiseaseisdefinedasanalanineaminotransferase(ALT)exceedingthreetimesthenormallevel,orthepresenceofchronichepatitisorcirrhosis.

3.3. Women of childbearing age• RifampicinandsomeARVdrugs(mainlyPIs)canreduceestrogenlevels,sooralcontraceptives

containingestrogenmaynotbeeffective.Formoreinformationoncontraceptionchoices,pleaserefertoProtocol9,Support for sexual and reproductive health of people living with HIV.

• Ifeffectivecontraceptionisensured,TB/HIV-coinfectedwomenmayreceivearegularTBtreat-ment regimen and the sameARV regimen asmen, includingEFV; otherwise,EFVmust beavoided.ABCisarecommendedalternativetoEFV.

3.4. Pregnant women• ThestrategyforinitiatingTBtreatmentandARTinpregnantwomenisthesameasinmenand

non-pregnantwomen(pleaseseeTable2insectionIII.2.2above).• CondomsshouldberecommendedtoTB/HIV-coinfectedpregnantwomenaswellastoallHIV

monoinfectedwomentoreduceriskofHIVsuperinfection(additionalinfectionwiththesameoranotherHIVsubtype)andotherSTIs.

• Mostfirst-lineTBdrugsaresafeforuseinpregnancy.Theexceptionisstreptomycin,whichisototoxictothefetusandshouldnotbeusedduringpregnancy(exceptformeningealinfections)orlactationduetothepotentialforseriousadversereactionsinnursinginfants(43).

• IfaTB/HIV-coinfectedwomandecidestocarryapregnancytoterm,sheshouldreceiveARVprophylaxisforpreventionofmother-to-childtransmission.ForfurtherinformationpleaserefertoProtocol 10,Prevention of HIV infection transmission from HIV-infected mothers to their in-fants.

• IfpropercasemanagementofTBandARTiscarriedout,themonitoringoftreatmentshouldbethesameasforotheradults.

3.5. Injecting drug usersTheclinicalmanagementofTB/HIVinIDUsischallengingandrequiresmoreeffortduetothefollowingfactors:• interactionofTBandARVdrugswithillicitdrugsandresultantincreasedhepatotoxicityinthose

IDUsreceivingopioidsubstitutiontherapy;• adecreaseinmethadonelevels(33–68%)orwithdrawalcausedbyrifampicin(themethadone

dosemayneedtobeincreased);• largerlikelihoodofcoinfectionwithhepatitisCand/orB,andthereforeofpotentialdruginterac-

tionswithhepatitisdrugs;• decreasedadherencelevels;and• decreasedaccesstothehealthcaresystem.

Collaborationwithharm-reductionprogrammes(44, 45)maybeessentialinorganizingeffectiveoutreachservicessuchaseducation,screening,TBpreventivetreatment,directlyobservedtreat-ment(DOT)forTBandthetracingoftreatmentdefaulters.

Itisimportanttokeepinmindthefollowing.• RifampicinshouldnotbeadministeredwithLPV/r,NFVorSQVinpatientsreceivingmetha-

donesubstitution therapy.Rifabutin isanoption,administeredas150mg3 times/weekwith

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LPV/ror300mg3times/weekwithNFV.• RifabutinshouldnotbeusedtogetherwithSQV.

Formoreinformation,pleaserefertoProtocol5,HIV/AIDS treatment and care for injecting drug users.

4. Monitoring TB/HIV-coinfected patients

4.1. Monitoring TB treatmentFormostpatients,unlessthereisdrugresistance,TBtreatmentiseffective,andtheirclinicalstatusimprovesstartinginthesecondorthirdweek.InTBpatientswithadvancedHIVinfectionorwithlatediagnosesforbothdiseases,aclinicalorradiologicalworseningmaybeobserved.Moreover,treatmentwithnormallyeffectiveTBdrugsmaybeunable to reverseclinicalcourse in the latestagesofHIV.

Duringtheinitial2–4weeksofTBtreatment,duringwhichpatientsarepreferablyhospitalized,acompleteclinicalevaluationshouldbedoneatleastweekly.ALTmustbeassessedatleastonceattheendofthefirstmonth.Hepatotoxicitymaybeobservedinupto5–10%ofcoinfectedpatients.

Apatient’sabilitytoswallowapillsshouldbeverified,andadherenceshouldbecheckedregularly.Exceptionally,severechronicdiarrhoeacanberesponsiblefordrugmalabsorptionandtreatmentfailure;suchaconditionrequirestheuseofinjectableTBdrugs.Evenwithoutdiarrhoea,HIV-in-fectedpatientsmaynotabsorbrifampicinadequately.Incaseofseveregastrointestinalintolerance,whichoccurs inup to10%ofHIVpatients,priorityshouldbegiven toTB treatmentandARTstoppeduntilrecoveryfromgastrointestinalsymptoms.

TBtreatmentstopsattheendofthecontinuationphase.Thereisstillnotenoughevidencesupport-ingtheutilityofsecondaryTBtreatmentinpreventingfurtherrelapses.

ForpatientswhoadheretoTBregimens,theprognosisforTBitselfisgood.Exceptionsare:• patientswithMDR-TB,whoshouldbereferredtospecializedtreatmentcentresbecauseoftheir

complexmanagement;and• patientswhoarejustbeginningTBtreatmentatanadvancedHIV/AIDSstage.

4.2. Monitoring antiretroviral treatmentMonitoringpatientsreceivingARTshouldincludeclinicalsignsandsymptoms,immunologicalandvirologicalcriteria,andARVtoxicityandside-effects.AfterinitiationofART,immunereconstitu-tion inflammatorysyndrome(IRIS)canoccur,especially inseverely immunosupressedpatients.SuchworseningofclinicalHIV/AIDSdiseaseafterinitialimprovementmayoccurinuptoathirdofpatientswithTBwhohavestartedART.TheaveragetimeofonsetistwomonthsafterARTini-tiation,butitcanoccurasearlyasfivedaysafter.IRISisthoughttobetheresultofimmunerestitu-tionduetoadministrationofantiretroviraland/orTBdrugs.IRISismorecommonifARTisstartedearlyinthecourseofTBtreatment,andifthepatienthasaverylowCD4count(46, 47).

Theexacerbatedsignsandsymptomsareduetoamoreeffectivelocaltissuereactiontoinfection,duetoM. tuberculosisorsomeotheropportunisticinfection(s).Thesesignsandsymptomsincludeacombinationof:• highfever• occurrenceorenlargementofperipheralormediastinallymphadenopathy• expandinglesionsinthecentralnervoussystem• worseningofchestradiographicfindings.

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ThediagnosisofIRISshouldbemadeonlyafterathoroughevaluationhasalreadyexcludedotheretiologies,particularlyafailureoftheTBtreatment.Mostcasesresolvewithoutanyintervention,andARTcanbesafelycontinued.Seriousreactions,suchastrachealcompressionduetomassiveadenopathyorrespiratorytherapy,mayrequireashortcourseofsteroids.Prednisonemaybegivenatthedoseof20–60mg/dayforatleasttwoorthreeweeks,graduallydecreasingindoseoveratleastonemonth(48, 49).

ForinformationaboutARVdrugtoxicityanditsmanagementpleaserefertothesectionManage-mentofARVtoxicityandside-effectsinProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents.

PatientstreatedforTBandHIVshouldbefollowedregularlyforclinicalevaluationoftolerancetotreatment.TheteststobeperformedaresummarizedinTable7.

Table 7. Monitoring of patients on arV and tb treatment

AssessmentWeek Month

0 2 4 8 3 4 5 6 7 8 9 10 11 12

TBandHIVdiseasehistory X X

Physicalexamination X X X X X X X

Comorbidities X X X X

Gynaecologicalexamination X X X

Routinelaboratorytests:• haemoglobin• fullbloodcountwith

differentialandplatelets• liverfunctiontests(ALT,possibly

ASTandbilirubin)• creatinine• urine

X X X X X X

CD4count X X X X

Viralload(ifavailable) X X X X

ChestX-ray X X

Pregnancytest X X

Sputum-smearexaminationa X X X X X X

Adherence(bothTBandARTtreatment)

X X X X X X X X X X X X X X

aRequiredattheendofthethirdandeighthmonthonlywhenon8-monthTBtreatmentregimen.

4.3. Adherence to TB treatment and ARV treatmentAdherenceiscrucialforthesuccessofbothTBandARVtreatment.Patientswithpooradherenceareatveryhighriskfordevelopingdrug-resistantstrainsofM.tuberculosisandHIV.Drug-resistantTBandHIVareverydifficulttotreateffectivelyandcanbetransmittedtoothers.DOTisrecom-mendedtoreinforceadherencetoTBtreatment,combinedwithcontext-specificandpatient-sensi-tivesupport(50).ForART,morethan95%adherenceisrequiredtoachieveoptimalHIVsuppres-sionandtreatmentoutcome(51).Theimportanceofadheringtotreatmentandconsequencesofpooradherenceshouldbefullyunderstoodbypatientsandproperlycoveredduringpatientcounselling.

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AdherencetotreatmentofTBandHIV/AIDSshouldbecloselymonitoredandexploredateveryvisit.Theeffectivemanagementofadversereactionstodrugsisveryimportantandconsideredanessentialconditionforensuringadherencetotreatment(FormoreinformationonadherencepleaseseethesectionsAdherencetoARTandMonitoringadherencebothinProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents).

ForbothTBandART,adherencemaybechallenginginspecialpopulationgroups,suchasIDUs.(FordetailedinformationaboutfactorsinfluencingadherenceinIDUs,pleaserefertoProtocol5,HIV/AIDS treatment and care for injecting drug users.)

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IV. Identification of TB/HIV in infants and children

ChildrenareusuallyinfectedwithTBthroughcontactswithanadultoranotherchildwithsputumsmear-positivePTB,oftenafamilymember.Intheabsenceofinterventionstopreventitstransmis-sion,infantstypicallyacquireHIVwhenexposedtoHIV-infectedfluids(principallyblood)inuteroorduringlabour.

WithoutpreventiveTBtreatment,40–50%ofHIV-positiveinfantsand15%ofHIV-positiveolderchildrenwillpresentwithsymptomsofTBdiseasewithinoneortwoyearsofbecominginfectedwithTB.Ininfants,thetimebetweenTBinfectionandTBdiseasemaybeaslittleas6–8weeks.SpecialconsiderationsshouldbegiventoinfantsborntoHIV-positivewomenwhostartTBtreat-mentlessthantwomonthsbeforedelivery.Theseinfantsshouldbeevaluatedforsignsandsymp-tomsofcongenitalTBandbetreatedifappropriate.

Childrenolderthan7andadolescentsusuallydevelopadult-typepulmonaryTBdiseasewithclas-sicpresentation.Manychildrenyoungerthan4,however,showatypicalpresentationsofextrapul-monarydisseminationwithhepatomegaly,prolongedfever,lymphadenopathy,anaemiaandweightloss,clinicalmanifestationsofmoreadvancedphasesofimmunesuppression.

1. Identification of TB in HIV-infected infants and childrenDiagnosisofTB in infants andchildren isdifficult,whetherornot theyare infectedwithHIV,becausetheyrarelyhavecavitarypulmonarydiseaseanddonotproducesputumforbacteriologi-calexamination.Othermethodsofobtainingmaterial,suchasgastriclavage,canbeproblematic.Consequently,bacteriologicalconfirmationisusuallynotpossible,andthediagnosisofpulmonaryTBinchildrenisoftenpresumptive.ThediagnosisofTBinHIV-infectedchildrenisevenmoredif-ficult,asseveralHIV-relateddiseasesmaypresentinamannersimilartoTB,andtheinterpretationofthetuberculinskintestisalsolessreliable.TBdiagnosisisthusoftenbasedonacombinationofahistoryofcontactwithanadultTBinfectiouscase,TBclinicalsignsandsymptomsandtheresultsoftheinvestigations.SeeTable8(15).

Table 8. conditions linked to active tb disease in children

Suspected tuberculosis• AhistoryofcontactwithaconfirmedcaseofpulmonaryTB• Failuretoregainnormalhealthaftermeasles• Weightloss,coughandwheezethatdonotrespondtoantibiotictreatmentforrespiratorydisease• Painlessswellinginagroupofsuperficiallymphnodes

Probable tuberculosisSuspectedTBwithanyofthefollowing:• positive(≥5mm)indurationontuberculinskintest• suggestiveappearanceonchestradiograph• suggestivehistologicalappearanceonbiopsymaterial• favourableresponsetoTB-specifictherapy.

Confirmed tuberculosis• Detectionbymicroscopyorcultureoftuberclebacillifromsecretionsortissues• IdentificationoftuberclebacilliasMycobacteriumtuberculosisbyculturecharacteristics

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2. Identification of HIV in children with active TBHIVinfectionmaybesuspectedinchildrenwithTB.DiagnosisofHIVinfectionininfants<18monthsoldshouldbedoneusingtheHIVDNApolymerasechainreaction(PCR)test.Inchildren18monthsandolder, theELISAserological testfollowedbyaconfirmatorywesternblot test isrecommended.ForfurtherinformationpleaserefertoProtocol11,Paediatric HIV/AIDS treatment and care.

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V. Clinical management of TB/HIV in children

1. Treatment of TBTBtreatmentofHIV-infectedchildrenisapriorityandshouldstartassoonasactiveTBdiseaseisdiagnosed.

TherecommendedTBtreatmentregimensforchildrenarethesameasthoserecommendedforado-lescentsandadults(seeTable1insectionIII.2.2.1.above).Thedrugdosagesperkilogramofbodyweightarealsothesame(seeAnnex1).

2. Treatment of HIV/AIDS

2.1. Initiation of ARTInHIV-infectedchildrenwithconfirmedTBdisease,initiatingTBtreatmentshouldbeapriority.ARTshouldbeinitiatedassoonaspossible(52),takingintoconsiderationtheclinicalandimmu-nologicalcriteriasummarizedinTable9.

Table 9. strategy for initiation of art in HiV-infected children with active tb

Criteria TB.treatment ART

Paediatric.ClinicalStage.4a, b

Startimmediately

Startimmediately

StartARTsoonafterTBtreat-ment(2–8weeksafterstartingTBtreatment).

Paediatric.Clinical..Stage.3a

Advancedimmunodeficiencyc

Mildornoimmunodeficiencyd

ARTmaybedelayedandtheneedforitreassessedaftercom-pletionofTBtherapy.CloselymonitorresponsetoTBtherapy;ifthereisnoimprovement,con-siderstartingART.

aForpaediatricclinicalstaging,seeProtocol11,Paediatric HIV/AIDS treatment and care,Annex1.bAllchildrenwithClinicalStage4shouldbeinitiatedonART,regardlessofCD4criteria.cAdvancedimmunodeficiencyisassumedtobeaCD4percentageof5%abovetheage-specificCD4thresholdforsevereim-munodeficiency,oraCD4countof200–350cells/mm3forchildren≥5yearsofage(seeProtocol11,Paediatric HIV/AIDS treatment and care,Annex2).dMildornoimmunodeficiencyisassumedatCD4levelsabovethosedefiningadvancedimmunodeficiency(again,seeProtocol11,Paediatric HIV/AIDS treatment and care,Annex2).

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2.2. Recommended HAART regimentsTheARTregimensrecommendedforTB/HIV-coinfectedchildrendifferslightlyfromrecommen-dations forHIV-monoinfectedchildren.ThechoiceofART regimen is complicatedby the lim-itedoptionsforpaediatricdrugformulationsand/ordosinginformation(particularlyforchildrenyoungerthan3).2.3. Key considerations for ARV drugs• IncaseofZDVtoxicityorintolerance,stavudine(d4T)canbesubstituted.• IfNVPisadministeredconcomitantlywithrifampicin,potentiallivertoxicityneedstobemoni-

toredclinicallyandwithaliverfunctiontest.• EFVisnotcurrentlyrecommendedforchildren<3yearsofage,norshoulditbegiventosexual-

lyactivegirlswhodonotuseadequatecontraceptionorareinthefirsttrimesterofpregnancy.• FollowingcompletionofTBtreatment,itispreferabletomaintaintheARTregimenoutlinedin

Table10.

Table 10. Haart regimens for tb/HiV-coinfected children being treated with rifampicin

Age of child ARV drug classes ARV drug combination

<3years

Preferred3NRTIs

(triple-nukeregimen)ZDV+3TC+ABC

Alternative2NRTIs+NVP ZDV+3TC+NVP

≥3years

Preferred2NRTIs+1NNRTI ZDV+3TC+EFV

Alternative3NRTIs

(triple-nukeregimen)ZDV+3TC+ABC

2.4. Cotrimoxazole primary prophylaxis TB/HIV-coinfectedchildrenshouldreceivecotrimoxazoleprophylaxisduringthewholeTBtreat-mentphase,independentoftheirlevelofimmunesuppression.Forcotrimoxazoleformulationsanddosages,pleaseseeProtocol 11,Paediatric HIV/AIDS treatment and care, sectiononpreventionandmanagementofOIs.

3. Monitoring of TB/HIV-coinfected childrenRoutinemonitoringofTB/HIV-coinfectedchildrenandtheirresponsetotreatmentshouldincludemonitoringofclinicalsignsandsymptoms,laboratoryindicators,adherenceandgrowth(nutrition).Sputum-smearassessmentsshouldbeperformedthesameasforadults:week8,month5,month6,month8andmonth12afterinitiationofTBtreatment.

FormoreinformationontheclinicalmanagementofHIV/AIDSinchildren,pleaserefertoProtocol 11,Paediatric HIV/AIDS treatment and care.

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

Itisrecommended(52)thatthefollowingdatabecollectedonaregularbasis(e.g.monthly,quar-terlyorsemi-annually)attheclinicalleveltoimproveclinicalmanagementofTB/HIV-coinfectedpatientsandtomonitortheimplementationofcollaborativeTB/HIVactivities:• numberofregisteredTBpatients;• numberofregisteredTBpatientswhoaretestedforHIV;• numberofregisteredTBpatientstestingpositiveforHIV;• numberofHIVpatientsseenfortreatmentandcarewhoarescreenedforTBsymptoms;• numberofHIVpatientswhohaveTBinfection: ° numberofHIVpatientswithTBinfectionwhohavereceivedtuberculosispreventativetreat-

ment(TPT)withizoniazid;• numberofHIVpatientswhoarenewlydiagnosedwithTBdisease: ° numberofHIVpatientsnewlydiagnosedandregisteredwithTBdiseasewhohaveCD4≥350

cells/mm3; ° numberofHIVpatientsnewlydiagnosedandregisteredwithTBdiseasewhohaveCD4<350

cells/mm3; ° numberofHIVpatientsnewlydiagnosedwithTBdiseasewhohavereceivedcotrimoxazole

preventivetherapy2(CPT);• numberofHIV/TBpatientswhoarereceivingTBtreatment;• numberofHIV/TBpatientsreceivingbothTBtreatmentandART;3• numberofHIV/TBpatientsineachcategoryofTBtreatmentoutcome;4• numberofHIV/TBpatientswhohavedied, includingcauseofdeath(e.g.TB-relateddeaths,

otherHIV/AIDSrelatedmortalityornon-HIV/AIDSrelatedmortalitysuchasaccident,over-doseorsuicide).

2DefinedasatleastonedoseduringtheirTBtreatment.3IncludingthenumberofpatientswhohavestartedonARTorarecontinuingpreviouslyinitiatedARTduringorattheendofTBtreatment4Thisindicatorshouldbecalculatedforeachofthefollowingpossibleoutcomes:cure,treatmentcompletion,treatmentfail-ure,death,defaultandtransferout.FordefinitionsoftheseoutcomespleaserefertoTreatment of tuberculosis: guidelines for national programmes(53).

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Annex 1. TB drugs (adults, adolescents and children)

Table 11. recommended dosage of first-line tb drugs

Drug

Recommended dose

Daily dosea

(usual dose or range)Thrice-weekly dose

(usual dose or range)

Isoniazid(H) 5mg/kg 10mg/kg

Rifampicin(R)10mg/kg

(450mgif<50kg;600mgif≥50kg)

10mg/kg(450mgif<50kg;600mgif≥50kg)

Pyrazinamide(Z) 25mg/kg(20–30mg/kg)

35mg/kg(30–40mg/kg)

Ethambutol(E) 15mg/kg(15–20mg/kg)


Streptomycin(S) 15mg/kg(12–18mg/kg)


aWhenrifampicinisusedconcomitantlywithantiretroviraldrugsinTB/HIVpatients,adailyTBtreatmentregimenispreferred(20).

Table 12. recommended formulations of first-line tb drugs

Drug(s) Dose form Strength (mg)

Single drugs

Isoniazid(H) Tablet 100,300

Rifampicin(R) Tabletorcapsule 150,300

Pyrazinamide(Z) Tablet 400

Ethambutol(E) Tablet 100,400

Streptomycin(S) Powderforinjectioninvial 750,1000

Fixed-dose combinations

Isoniazid+rifampicin

TabletTabletTabletTabletorpackofgranulesTabletorpackofgranules

75+150150+30030+60150+150(thriceweekly)60+60(thriceweekly)

Isoniazid+ethambutol Tablet 150+400

Isoniazid+rifampicin+pyrazinamide Tabletorpackofgranules

75+150+40030+60+150150+150+500(thriceweekly)

Isoniazid+rifampicin+pyrazinamide+ethambutol Tablet 75+150+400+275

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Annex 2. ARV drugs (adults and adolescents)

Table 13. recommended formulations of first-line arV drugs

Drug(s) Recommended dose (mg)

NRTIs

Abacavir(ABC) 300BID

Didanosine(ddI)a 400OD(250if<60kg)or200BID

Lamivudine(3TC) 150BIDor300OD

Zidovudine(ZDV) 300BID

Tenofovir(TDF) 300OD

NNRTIs

Efavirenz(EFV) 600OD

PIs

Lopinavir/ritonavir+ritonavir(LPV/r+RTV) (400/100+300)BID

Saquinavir+ritonavir(SQV+RTV) (400+400)BID

aWhenddIisadministeredconcomitantlywithTDF,therecommendeddoseisddI250mgODforpatientswithabodyweightof>60kgand125–200mgODforpatientswithabodyweightof<60kg.

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Table 14. recommended arV formulations for tb/HiV-coinfected adults and adolescents

Drug(s) Dose form Strength

Single drugs

Abacavir(ABC) TabletOralsolution

300mg20mg/ml

Didanosine(ddI)

TabletSingle-dosepacketsofbufferedpowderfororalsolutionPaediatricpowderfororalsolution

Delayed-releasecapsules

25,50,100,150,200mg100,167,250mg

4-and8-ounceglassbottlescontainingrespectively2and4gdidanosine125,200,250,400mg

Lamivudine(3TC) TabletOralsolution

150,300mgfilmcoated10mg/ml

Zidovudine(ZDV)

TabletCapsuleOralsolution/syrupRetrovirIVinfusion/sterilesolutionforIVinfusion

250,300mg100mg50mg/5ml10mg/ml

Tenofovir(TDF) Tablet 300mg

Efavirenz(EFV) CapsuleTabletfilmcoated

50,100,200mg600mg

Lopinavir/ritonavir(LPV/r)TabletCapsuleOralsolution(contains42.2%alcohol)

200/50mg133.3/33.380/20mg/ml

Saquinavir(SQV) CapsuleTablet

200mg500mg

Ritonavir(RTV) CapsuleOralsolution

100mg80mg/ml

Fixed-dose combinations

Zidovudine+lamivudine(ZDV+3TC) Tabletfilmcoated 300+150mg

Zidovudine+lamivudine+abacavir(ZDV+3TC+ABC)

Tablet 300+150+300mg

Tenofovir+emtricitabine(TDF+FTC) Tablet 300+200mg

Abacavir+lamivudine(ABC+3TC) Tablet 600+300mg

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4 Management of Tuberculosis and HIV Coinfection

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