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ContentsI. Introduction .............................................................................................................................393

II. Laboratory diagnosis of HIV ................................................................................................394 1.Diagnosisofchildren<18monthsofage...........................................................................394 1.1.Diagnosisinnon-breastfeedinginfants........................................................................394 1.2.Diagnosisinbreastfeedinginfants...............................................................................396 1.3.DiagnosisininfantsexposedtoARVprophylaxis.......................................................396 1.4.DiagnosisininfantsborntomothersonART..............................................................396 2.Diagnosisinchildren≥18monthsold................................................................................396

III. Clinical management of HIV-infected children .................................................................397 1.ClinicalandlaboratoryevaluationsofHIV-infectedchildren............................................397 2.Nutritionalsupport..............................................................................................................397 3.Counsellingcaregivers........................................................................................................398 3.1.Considerationsofadolescentneeds.............................................................................398 4.ARTininfantsandchildren................................................................................................399 4.1.Immunological,age-specificcriteriaforinitiationofART..........................................400 4.2.First-lineHAARTregimens.........................................................................................400 4.3.HAARTregimensinspecialcircumstances................................................................401 4.4.ARTininfantsexposedtoARVs.................................................................................401 4.4.1.ExposurethroughPMTCT.................................................................................401 4.4.2.ContinuingexposureduetomaternalARTduringbreastfeeding......................402 4.5.ARVdosageandage-doseadjustment.........................................................................402 4.6.Adherence....................................................................................................................402 4.7.ARTfailure...................................................................................................................402 4.7.1.Immunologicalfailure........................................................................................402 4.7.2.Virologicalfailure..............................................................................................402 4.7.3.Clinicalfailure...................................................................................................403 4.8.Second-lineARTregimens..........................................................................................403 4.9.Strategiesintheeventofsecond-linetreatmentfailure...............................................403 5.MonitoringchildrenwithHIV............................................................................................404 5.1.RoutinemonitoringofpatientsbeforeART.................................................................404 5.2.RoutinemonitoringofpatientsonHAART.................................................................404 5.2.1.Clinicalmonitoring............................................................................................404 5.2.2.Laboratorymonitoring.......................................................................................404 5.3.Immunereconstitutioninflammatorysyndrome..........................................................404 5.4.MonitoringARVtoxicity.............................................................................................404 5.4.1.ClinicalsignsofARVtoxicityanditsmanagement..........................................406 5.4.2.ARVsubstitutioninfirst-lineregimensduetotoxicity......................................407 5.5.Monitoringadherence..................................................................................................408 5.6.Nutritionalandgrowthmonitoring..............................................................................409 5.7.Developmentalassessment..........................................................................................409

IV. Prevention and management of major opportunistic infections.......................................410 1.Tuberculosis........................................................................................................................410 2.DisseminatedmycobaceteriosisotherthanTB..................................................................410 3.Pneumocystis jiroveciipneumonia......................................................................................411 4.Bacterialinfections(non-mycobacterial)............................................................................412 5.Toxoplasmosis.....................................................................................................................413

6.Fungalinfections.................................................................................................................415 6.1.Candidiasis...................................................................................................................415 6.1.1.Oropharyngealcandidiasis.................................................................................415 6.1.2.Oesophagealcandidiasis....................................................................................415 6.1.3.Candidaemia......................................................................................................416 7.Viralinfections....................................................................................................................417 7.1.Cytomegalovirus..........................................................................................................417 7.2.Varicella-zostervirus...................................................................................................418 7.3.Herpessimplexvirus...................................................................................................419

V. Paediatric HIV pain management .........................................................................................421 1.Background.........................................................................................................................421 2.Painmanagementstrategies................................................................................................421

VI. Suggested minimum data to be collected at the clinical level ...........................................422

Annex 1. Revised WHO clinical staging of HIV/AIDS for infants and children...................424

Annex 2. WHO classification of HIV-associated immunodeficiency in infants and children ................................................................................................................426

Annex 3. ARV dosage ranges .....................................................................................................428

Annex 4. Developmental assessment checklist .........................................................................430

References ....................................................................................................................................431

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Paediatric HiV/aidS treatment and care

I. Introduction

TheincreasingnumberofreportedpaediatricAIDScasesinEuropeancountries(1)demandsurgentactiontoimprovesurvivalandqualityoflifefortheaffectedchildren.

ThecorecomponentoftreatmentandcareofinfantsandchildreninfectedwithHIVisprovisionofantiretroviraltreatment(ART).OptimalARTincreasesthelengthandqualityoftheirlives.

ThegoalsofpaediatricARTarethesameasforadultsandadolescents,theprolongationoflifeandimprovementofitsquality(seeProtocol1Patient evaluation and antiretroviral treatment for adults and adolescents).

PolicyforARTinpaediatricHIV/AIDScasesshouldbebasedonthefollowingprinciples.• Antiretroviral(ARV)treatmentshouldbeavailableaspartofacomprehensivepackageofpae-

diatricHIVcare.• It should be consistent with Protocol 10 Prevention of HIV transmission from HIV-infected

mothers to their infants.• PaediatriciansshouldprovideroutinecareandcollaboratecloselywithpaediatricHIVspecial-

iststomonitorHIVprogressionandtheneedforART.• Acontinuumofcareshouldbeassuredduringchildhood,duringtransitiontoadolescenceand

adulthoodandinlinewithfuturetreatmentandcareforadolescentsandadults(seeProtocol1,Patient evaluation and antiretroviral treatment for adults and adolescents).

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

II.LaboratorydiagnosisofHIV

1. Diagnosis of children ‹18 months of age Inchildren<18months,virologicalassaysarerecommendedfordetectingplasmaHIVDNA(2),plasmaHIVRNA(3–7)andimmunecomplex-dissociated(ICD)p24antigen(8–10).Virologicaltestshaverecentlybecometechnicallyeasier,lessexpensiveandmorereliable.

1.1. Diagnosis in non-breastfeeding infantsSeethealgorithminFig.1below.• TheprobabilityofHIVdiagnosisbyDNAassayincreaseswithage;38%ofinfectedchildren

havepositiveDNAPCRtestsbytheageof48hours.Byage28days,DNAPCRhas98%sen-sitivity(11)and99%specificityinidentifyingHIVpro-viralDNA(12).

• Infantswithapositivevirologicaltestatage48hoursmayhaveanintrauterineinfection.• Infantswithanegativevirologicaltestduringthefirstweekoflifeandsubsequentpositivetests

haveanintrapartuminfection(13).• HIVinfectioncanbediagnosedbyHIVDNAorRNAdetectioninmostinfectednon-breast-

feedinginfantsbyage1monthandinvirtuallyallinfectedinfantsbyage6months.• Bloodsamplesfromtheumbilicalcordshouldnotbeusedfordiagnosticevaluationsbecauseof

potentialcontaminationfrommaternalblood.• A first virological test shouldbeperformedon infants about48hours afterdelivery, before

mother and infant aredischarged.1Apositivevirological test (usuallyDNA)means that theinfantis“provisionallyHIV-infected”;anegativeresultatthisstagesuggestsanindeterminantstatus.

• Thesecondvirologicaltestshouldbedoneataround6weeksofage.Thisisthekeytestforinfantswhotestednegativewiththefirstvirologicaltest.Ifthistestisnowpositive,usuallytest-ingalgorithmsrequireconfirmationbyarepeattestonaseparatespecimenforconfirmation.

• AsecondpositivevirologicalresultindicatesthattheinfantisHIV-infectedandshouldbeclini-callyevaluatedtodevelopamanagementstrategy,seesectionIIIbelow.

• Ifasecondvirologicaltestisnegativetheinfantisassumedtobeuninfected,however,regularmonthlymonitoringforsignsofHIVinfectionshouldbeconductedandifresourcesareavail-able,athirdvirologicaltestmaybeofferedatageof3months.

1Insettingswithlimitedresourcesoraccesstovirologicaltestsitmaybemoreefficientandcosteffectivetoconductinitialvirologicaltestingat6weeksorage,asHIVinfectionstatuscanbereliablydeterminedinalmostallchildrenatthisstage(fol-lowalgorithm1fromwhere2ndtestbegins).

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aThismaybethefirstdiagnosticalgorithmiftestingattheageof48hoursisnotavailable.bUsualconfirmatorytestshouldbefollowedonanewspecimen.

1st Virological test(48 hours after birth)

positive negative

Status:provisionally HIV-

infected

2nd Virological testUsually performed from

6 weeks of agea

positiveb negative

Status:Indeterminant

Status:assumed healthy

Confirmation &clinical evaluation;HIV treatment and

care

Monitor for signs of HIVinfection

If signs appearbefore 18

months, repeatvirological test

Status:HIV-infected

If resources areavailable, repeatvirological test at

age 3 months

Fig 1. HiV virological diagnosis in non-breastfed infants born to HiV-infected mothers

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1.2. Diagnosis in breastfeeding infants• WHOEUROdoesnotrecommendbreastfeedingforinfantsborntoHIV-infectedmothers.• Ifalternativefeedingisnotavailableandaninfantisbreastfeeding,virologicalassayscanbe

performedanytime.Iftheresultisnegativethenitshouldbeconductedatleastsixweeksaftercompletecessationofbreastfeeding,toconfirmthattheinfantisnotHIV-infected.

1.3. Diagnosis in infants exposed to ARV prophylaxis• ARVprophylaxistoavoidmother-to-childtransmission(MTCT)doesnotaffectHIVDNAtest

results.HIVDNAremainsdetectableintheperipheralbloodmononuclearcellsofanHIV-in-fectedchild.

• ThesensitivityofHIVRNAmaybeaffectedbyARVprophylaxis.Therefore,iftheHIVRNAassaywasnegativewhiletheinfantwasreceivingprophylaxis,itshouldberepeatedatleasttwoweeksafterprophylaxishasbeencompleted.

1.4. Diagnosis in infants born to mothers on ART• InfantsofmotherswhoareonARTorhavealoworundetectableviralloadatdeliveryanddo

notbreastfeedcanbeconsideredatlowriskforacquiringinfection(14).• GiventherelativelyhighARVlevelsfoundinbreastfeedinginfants,itisnotknownwhether

maternalARTduringbreastfeedingaffectsRNAdetectionintheinfant.• DNAdetectionisunaffectedbymaternalART.

2. Diagnosis in children ≥ 18 months old• Bytheageof12months,mostuninfectedHIV-exposedchildrenwillhavelostmaternalanti-

bodies.HIVantibodytestingwithapositiveresultinachildatthisageusuallyindicatesHIVinfection(96%specificity)(15).

• DefinitiveHIVdiagnosisinchildren≥18monthsold(whetherHIVexposureisknownorun-known)canbeperformedwithantibodytests (ELISAorrapid test),whileWesternBlothasbeenusedinthepast,confirmationofHIVstatusismorereliablyestablishedwithvirologicaltesting.

• SomeclinicalconditionsareveryunusualintheabsenceofHIVinfection(Pneumocystispneu-monia, oesophageal candidiasis, lymphocytic interstitial pneumonitis (LIP),Kaposi sarcomaandcryptococcalmeningitis).Diagnosisofsuchconditionsandotherstage3and4clinical(seeAnnex1)diagnosessuggestsHIVinfectionandindicatestheneedforanHIVantibodytest.

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III.ClinicalmanagementofHIV-infectedchildren

1. Clinical and laboratory evaluations of HIV-infected childrenAllinfantsandchildrenwhoarediagnosedwithHIVinfectionshouldundergoclinicalandlabora-toryevaluationstodeterminethestageofHIVclinicaldiseaseandimmunodeficiency,eligibilityforARTandothermorbiditiesorissuestobeaddressed.Thisbaselineassessmentwillalsoprovideanopportunitytoinitiatecotrimoxazolepreventivetherapyandshouldserveasanopeningtooffercounsellingandsupporttoinfectedchildrenandtheirparents/caregivers.

ClinicalandlaboratoryevaluationofchildrenwithHIVshouldincludethefollowing:• currentclinicalsignsandsymptomstoestablishclinicalstage(seeAnnex1);• exposuretoandriskforcoinfections(tuberculosis(TB),hepatitisB,hepatitisC);• identificationofcomorbiditiesandmedicationstakentotreatthem;• historyofpreviousexposuretoARVs,includingdrugsusedforpreventionofmother-to-child

transmission(PMTCT);and• laboratorytests: o completebloodcount; o CD4cellcount(absoluteandpercentageforchildren<6yearsold); o liverenzymes(ALTandAST); o additionaltests:bilirubin,creatinine,urinalysis,glucose; o testingforTB,hepatitisBandC(ifatrisk); o pregnancytestsforadolescentgirls.

Otherevaluationstobeundertakenduringthevisit:• anthropometricalmeasurements:weight,height/lengthandheadcircumference;• nutritionalassessment,including: o typesoffoodsconsumedandestimatedamounts; o appetiteandlengthofeatingtime; o problemsassociatedwithfoodintake; o identificationofcaregiverwhofeedsthechild.• socialassessment: o generalhouseholdhygieneandaccesstosafewater; o availabilityofasecurerefrigeratorformedicationstorage; o theabilityoffamilymembersandothercaregiverstomonitoradherence; and• psychologicalstatusofbothcaregiverandchildandacognitiveassessmentofthechild.

2. Nutritional supportNutritionalsupportshouldincludeearlyeffortstoensureadequatenutrientintake,basedonlocallyavailableandaffordablefoodsandtheprovisionofmicronutrientsequivalenttotherecommendeddailyallowance(RDA)(16, 17).• Increasingtheenergyintakeofasymptomaticinfantsandchildrenby10%oftheRDAfortheir

ageandsexisrecommended.• Theenergyintakeofinfantsandchildrenwhoaresymptomaticorrecoveringfromacuteinfec-

tionsshouldbeincreasedby20–30%oftheRDA(18).• Such requirementsareminimalandmayneed tobeaugmented forchildrenwithnutritional

deficiencies(19).

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• Itisnotnecessarytoincreaseproteinintakebeyondthatrequiredforanormallybalanceddiet(12–15%ofthetotalenergyintake)(18).

• VitaminAsupplementsshouldbegivenaccordingtotheWHOrecommendedhigh-dosepre-ventionscheduleforchildrenathighrisk2fordeficiency(20–22).

• ClinicalobservationsindicatedthatinfantswithAIDSdefiningclinicaldiseasecommonlyhavetemporarylactoseintoleranceandcow’smilkprotein(CMP)intolerance.Expertsusuallyrec-ommendthatifthechildpresentswithseverediarrhoea,specialmilkformulaeandlactoseCMPfreemilk,ifavailable,canalleviatetheproblem.

3. Counselling caregiversParentsand/orothercaregiversofHIV-infectedchildrenshouldbecounselledonseveralmatterspriortostartingchildrenonART. AdherencetoARTisthekeytosuccessfultreatment.Itpredictsandinfluencesthevirologicalandclinicalresponsetotreatment(23), anditsimportancemustbecommunicatedtocaregivers.Theaimsofsuchcounsellingshouldinclude:• establishingtrustwiththecaregiverandsettingmutuallyacceptablegoalsforcare;• obtainingexplicitagreementofthechild’sneedfortreatmentandtreatmentadherence;• identifyingandaddressinganyofthecaregiver’spsychologicalissuesthatmaydecreaseadher-

ence;• identifyingaback-upcaregiverwhocanhelpwithadherencesupport;• educatingthepatientand/orcaregiveraboutthecriticalimportanceofmaintainingatleast95%

adherence,thelinkbetweenpartialadherenceandresistance,andthewaythattemporarynon-adherencecanpermanentlylimitchoices;

• providinginformationaboutpossibleside-effectsofARVsandtheirmanagement;• emphasizingtheneedforfollow-upvisitsandschedulingthem;and,• psychologicalandsocialissuesshouldbediscussedwithcaregiversandappropriatereferrals

shouldbeoffered,including: o socialandrightsbasedservices; o peersupportgroupsforparents/caregiversandforchildren.

Propernutritionisalsoaprimecounsellingissue,includingtheoptimaluseoflocalfoods,appropri-atenutritionsupplementsandthenutritionalmanagementofHIV-relatedconditionsaffectingtheappetiteandtheabilitytoeat(seesectionIII.2above).

Parentsshouldbeawareofdevelopmentalmilestonesandstagesofgrowththatinfantsandyoungchildrenshouldbereachingandtheimportancefor thesetobeobservedanddiscussedwiththephysician(seesectionsIII.5.6andIII.5.7).

Prevention of infections should also be addressed, including Pneumocystis jirovecii pneumonia(PCP)prophylaxis(seesectionIV.3below)androutineimmunizations(seeProtocol12,Immuniza-tion of people living with HIV and people at risk for HIV infection).

3.1. Considerations of adolescent needsOnceachildreachesadolescencethereareotherconsiderationsthatneedtobetakenintoaccountandaddressedduringcounsellingtoensurethatappropriatetreatmentandcarecontinuetobepro-vided.Duringthistimetheypassthroughphysical,psychologicalandsexualmaturation,allwhichhaveimplicationsinthecontinuumoftheirtreatmentandcare.Thefollowingissuesnowneedtobedscussedwithandunderstoodbytheadolescent:• disclosureoftheHIVstatustotheadolescentifithadnotalreadybeendone,thisshouldinclude

basicinformationrelatedtoHIV/AIDS;• preventionstrategiesinlightofimpendingsexualactivityandfertility,includinginformation

onsexualandreproductivehealthandPMTCT(refer toprotocols9,Support for sexual and

2Childrenwithsevereinfectionsorsevereprotien-energymalnutrition.

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reproductive health in people living with HIV,and10,Prevention of HIV transmission from HIV infected mothers to their infants;

• preventionofopportunisticinfectionsandtheneedtotreattheminanexpedientmanner;• transitionfrompaediatrictoadultcare,andthattheremaynowbeachangeinhealthcarepro-

vidersaswellasinARVregimens;• theimportanceofcontinuingtoadheretotreatmentandconsequencesofnon-adherence;• toxicityandsignsofit;and• waystoaddresspossiblestigmaanddiscrimination.

4. ART in infants and childrenThecriticalissueinclinicallymanagingHIV-infectedchildreniswhentoinitiatelifelongART.TheeffectivenessofHAARTinreducingHIV-relatedmorbidityandmortalityininfantsandchildreniscomparabletothatobservedinadults(24).However,thereareuniqueconsiderationsforHIV-infectedinfantsandchildren,including:• exposuretoZDVandNVP(25–27)andotherARVstakenduringpregnancy,whichmayresult

inARVresistance;• age-dependentdifferencesinimmunologicalmarkers(e.g.CD4percentageisusedforchildren,

notCD4count);• age-dependentpharmacokineticaldifferences;• difficultiesadheringtolong-termcombinationtreatment;• difficultiestakingmedicationduringsleepinghoursoratschool; and• unwillingnessofchildrenandadolescentstotakemedication.

ChildrenshouldbestartedonARTwhentheyhaveeitheranAIDS-definingillnessorsevereim-munological failure (seeTable1).Thedecision to startARTshouldbemadeaccording tobothCD4percentageandage.ItisnowpossibletodeterminetheexactriskofprogressiontoAIDSordeathoverthenextcalendaryearbasedonthesefactors(ariskcalculatorisavailablefromtheHIVPaediatricPrognosticMarkersCollaborativeStudy(28)).Infantswhoareathighriskforclinicalprogression,particularlyforHIVencephalopathy,shouldstartARTwithahigherCD4percentagethanolderchildren.InitiationofARTinchildrenwithaconfirmedHIVdiagnosisshouldbebasedontheWHOguidelinesforclinicalstagingofpaediatricHIV/AIDS(seeAnnex1),immunologicalcriteriaandthePaediatricEuropeanNetworkforTreatmentofAIDS(PENTA)guidelines3(29).

Table 1. criteria for initiation of art in infants and children

WHO clinical paediatric stageAge-specific treatment recommendations

<12 monthsa ≥12 months

1 Treatall CD4-guidedtreatmentb



4c TreatallaTherecommendationtotreatallchildren<12monthsdiffersfromWHOglobalguidelines.EuropeanpaediatricHIVexpertsgenerallybelievethatallinfantsdiagnosedwithHIVinfectioninthefirstyearlifeshouldbetreated,however,additionalre-searchisinneedtoconfirmthisrecommendation.bForCD4guidance,refertoTable2.cStabilizeanyopportunisticinfectionpriortoinitiatingofARVtreatment.Source: adaptedfromglobalguidelines,WHO(30).

3Whereverpossible,childrenwithHIVinEuropeshouldbecaredforincollaborationwithamemberofthePENTAnetwork.Fullcontactdetailsareathttp://www.ctu.mrc.ac.uk/penta.

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4.1. Immunological, age-specific criteria for initiation of ART• Immunologicalmarkerssupplementclinicalassessmentandshouldthereforebeusedincombi-

nationwithclinicalstaging.• ThethresholdCD4levelsforsevereimmunodeficiency,asindicatedinTable2below,arede-

rived from longitudinal data onHIV-infected infants and children and indicate the levels atwhichARTisrequired.IngeneralCD4percentageisamoreaccuratemarkerinchildrenagedunder5yearsandCD4countisthebetterguideforchildrenagedover5years.

• WheretheCD4percentageisnotavailable,absoluteCD4countthresholdsmaybeused• Forchildrenovertheageof5,thesamecut-offvalueasinadults–i.e.200–350cells/mm3–can

beused.ThereisamarkedincreaseinriskofAIDSwhentheCD4countdropsbelow200,sothisshouldbeavoided.

• Adropbelowthresholdvaluesshouldbeavoided,asitsignificantlyincreasestheriskofdiseaseprogressionandmortality.ARTshouldbeinitiatedbythesecut-offlevels,regardlessofclinicalstage.

• For childrenwithpulmonaryTB, the result ofCD4measurement and clinical status shouldguidewhetherARTisurgentlyrequiredorcanbedelayed(refertoProtocol4,Management of tuberculosis and HIV coinfection).SeeAnnex2foranoverviewoftheproposedrevisiontotheimmunologicalclassification.

Table 2. cd4 criteria for initiation of art

Immunological marker

Recommended threshold levels for initiating ART

≤11 months 12–35 months 36–59 months ≥5 yearsa

CD4%and/orCD4count ≤25%(≤1500cells/mm3)

≤20%(≤750cells/mm3)

≤15%(≤350cells/mm3)

≤200cells/mm3(≤15%)

aStartingat5yearsofageCD4cellcountisamoreaccurateindicationforinitiationoftreatment.Source:adaptedfromWHO(30).

HIVprogressionismorerapidinchildrenthaninadults.ThepredictivevalueofspecificHIVRNAlevelsfordiseaseprogressionisdifficulttointerpret,particularlyforinfants,soanassessmentofviralload(VL)isnotconsiderednecessarybeforestartingtreatment.However,VLremainsausefulmeasurementoftreatmentresponseandshouldbeperformedbeforestartingARTandatonemonthandthreemonthsoftreatment,ifpossible.TheaimoftreatmentistoachieveanundetectableVLlevel(nowusuallydefinedas<50copiesHIV/mlplasma),whichstopsviralreplicationandreducesthechancesofresistancetotheARTcombinationbeingused.

TheriskofprogressiontoAIDSordeathwithin12monthsbasedonage,CD4%orCD4countorviralloadmaybeausefulascomplementaryinformationtoclinicalandlaboratoryindicatorswhenmakingadecisiontoinitiatetreatment.Thismaybecalculatedbyusingtheriskcalculatorthatcanbeaccessedathttp://www.ctu.mrc.ac.uk/penta/hppmcs(31).

4.2. First-line HAART regimensThechoiceoffirst-lineARVregimensforinfantsandchildrenfollowsthesameprinciplesasforadults,withseveraladditionalconsiderations:• thepatient’sage• thesuitabilityofdrugformulations• theside-effectprofile• thepossibilityofmaintainingfuturetreatmentoptions• anticipatedpatientadherence• coexistingconditions(coinfections,malnutrition,metabolicabnormalities)• riskofpregnancyinadolescentgirls• potentialdruginteractions.

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Intheabsenceofresistanceassays,childrenwhoreceiveARVprophylaxisshouldfollowthestand-ardfirstlineARTregimensindicatedinTable3.

Table 3. First-line art for infants and children

Age ARV drug classes ART regimens

<3years(or<10kg) 2NRTIs+1NNRTI ABC(orZDV)+3TCa+NVPb

≥3years 2NRTIs+1NNRTI ABC(orZDV)+3TCa+EFVb,c

aTheABC+3TCcombinationisveryeffectiveforART-naivechildren.PENTA5followupdataclearlyconfirmsthesuperi-orityofthisregimen(http://www.ctu.mrc.ac.uk/penta/trials.htm(32, 33).d4Tshouldbeavoidedduetotheincreasedriskoflipodystrophy(34, 35).bEFVisnotcurrentlyrecommendedforchildren<3yearsofageor<10kg,andshouldnotbegiventopost-pubertalgirlswhoareeitherinthefirsttrimesterofpregnancyoraresexuallyactiveandnotreceivingadequatecontraception.EFVispreferredoverNVPinchildrenolderthanthreeyears.cNVPshouldbeavoided inpost-pubertalgirls (consideredadults for treatmentpurposes)withbaselineCD4absolutecellcounts>250cells/mm3.

4.3. HAART regimens in special circumstancesThetriple-NRTIregimencanbeconsideredanalternativeoptionthatsimplifiesinitialtreatmentinspecialcircumstances.Thepotencyofthisregimenwithhighviralload,whichiscommoninin-fantsinfectedinuteroisamatterofconcern,ashasbeendemonstratedinadultstudies(36–38),andthereforeitsuseiscurrentlyrecommendedtobeconsideredforspecificsituationsincludingto:• pregnantadolescentswithCD4counts>250cells/mm3,forwhomNVPandEFVarecontrain-

dicated;and• adolescentswithanticipatedordocumentedpooradherence(ifregimenisavailableasafixed-

dosecombination(FDC)).

Table 4. alternative art

ARV drug class ART regimen

3NRTIs ZDV+3TC+ABC

4.4. ART in infants exposed to ARVsThereisapossibilityofinfantsandchildrendevelopingresistancetocertainARVsinutero,intra-partumorpostpartum(duringbreastfeeding).

Aresistantviruscanbetransmittedby:• ARV-naivemotherswhowereinfectedwithresistantHIVviruses;• mothersexposedtoARVsbeforebecomingpregnant;or• mothersexposedtoARVsduringpregnancy,whetherfortheirownhealthorforMTCTprophy-

laxis.

Thefrequencyofsuchtransmissionhasnotbeenwelldocumented;consequently,therecommendedARTregimensremainthesameasforinfantsnotexposedtoARVs.

4.4.1. Exposure through PMTCT

• IfNVPor3TChasbeenusedforPMTCT,eitheraloneorinatwo-drugregimen,asinglepointmutationcanresultthatmaybeassociatedwithresistancetotheseARVs(39, 40).Furtherre-searchisneeded.

• Childrenwhohavepreviouslyreceivedsingle-doseNVPor3TCaspartofPMTCTorotherARVsshouldnotbedeniedaccesstolife-sustainingART.

• Itisnotyetclearwhethertriple-NRTIregimensofferbenefitsinsuchsituations.• Thestandard2NRTIs+1NNRTIfirst-lineregimenisrecommended(30).

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4.4.2. Continuing exposure due to maternal ART during breastfeeding

• AlthoughsomeARVs(NVP,ZDVand3TC)areknowntobepresentinbreastmilk,theconcen-trationandquantityingestedbyinfantsislessthantherapeuticlevels(41, 42).

• IfabreastfeedinginfantisillenoughtorequireART,theadministrationofARVsatstandardpaediatricdosesshouldbeinitiated,regardlessofwhetherthemotherisreceivingART.

• Thestandard2NRTIs+1NNRTIfirst-lineregimenisrecommended.

4.5. ARV dosage and age-dose adjustmentEverythreemonths,theARVdrugdosageshouldbecheckedandadjustedaccordingtothechild’sweight;otherwise,thereisariskofunderdosinganddevelopingresistance.Dosesarecalculatedeitheronamilligramperkilogrambodyweightormilligrampersquaremeterbodysurfacebasis.Standardizationis important,sothatnon-expertpersonnelcansafelydispenseand/orcheckcor-rectdosagesforchildren.Itissensibleclinicalpracticetoroundupdosesintoeasierdosesfortheparents.Itisbettertooverdosebyupto10%asthechildrapidlygrows.ForARVdosagespleaserefertoAnnex3(30).

4.6. AdherenceAdherenceisthekeytoachievinganeffectiveclinical,immunologicalandvirologicalresponsetoART,anditshouldbenolessthan95%oftheprescribeddosage(23, 43, 44).AninitialinterventionstrategytoimproveadherenceisdescribedinsectionIII.3aboveoncounsellingofcaregivers,andadherencemonitoringisdescribedinsectionIII.5.5below.

Medicationstrategiestoimproveadherenceinclude:• choosingthesimplestregimen,withalowerdosingfrequencyandnumberofpills;• prescribingcarefullytoavoiddruginteractions;• simplifyingfoodrequirementsforadministrationofmedication;• informingpatientsandcaregiversofpossibleside-effects,andanticipatingandtreatingside-ef-

fects;and• usingthebest-tastingliquidmedicationifpossible,andintroducingtabletsassoonasfeasible

orifliquidmedicationisnotavailable.

4.7. ART failurePooradherence,inadequateARVdosageorpotency(23, 43, 45, 46)andpharmacokineticproblems(47)canallcontributetotreatmentfailure.Childrenshouldhavebeentakingtheirfirst-lineregi-menforatleast24weeksandadherencedeemedadequatebeforetreatmentfailureissuspected.Theclinicalcriteriafortreatmentfailureshouldbesupportedwithimmunological(CD4)criteria.

4.7.1. Immunological failure

Intreatmentfailure,childrenonARTpersistatorbelowtheage-relatedCD4thresholdforinitiatingtreatment(seeTable2above).FailureischaracterizedbyaninitialimmunerecoveryafterinitiationofART,followedbyadropinCD4measurementstovaluesatorbelowtheirage-relatedthresholdforinitiationoftreatment.PreviousCD4valuesarethusneededtodefinetreatmentfailureusingimmunologicalcriteria.

4.7.2. Virological failure

Thedefinitionofvirologicaltreatmentfailureismorecomplex,andconsensusonithasnotyetbeenreached.TheoverallaimoftreatmentistoreduceVLtolevelsbelowthelowestdetectionthreshold(<50copies/ml)andtomaintainitaslongaspossible.Alargenumberofchildrenontreatment,however,haveadetectableVLbetween1000and50,000copies/ml,butcontinuetohaveexcellentclinicalresponseandmaintainhighCD4%values.Sincenoclearsinglevirologicalthresholdcanberecognizedtopromptswitchingtosecond-lineART,thefinaldecisionshouldbetakenbaseduponconsiderationoftheclinicalandimmunologicalstatusofthechild.

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4.7.3. Clinical failure

Thefollowingareconsideredindicativeoftreatmentfailure:• developmentofneworrecurringStage3or4events(seeAnnex1)atleast24weeksafterinitia-

tionofafirst-lineregimen;• lackofordeclineingrowthrateinchildrenwhoshowaninitialresponsetotreatment,despite

adequatenutritionalsupportandwithoutotherexplanation;• lossofneuro-developmentalmilestones(presenceoftwoormoreofthefollowing:impairment

inbraingrowth,declineincognitivefunctionandclinicalmotordysfunction(48));and• newopportunistic infections, newmalignancies, recurrence of refractory oral candidiasis or

recurrenceofoesophagealcandidiasis.

Clinical disease progression should be differentiated from immune reconstitution inflammatorysyndrome(IRIS),pleaseseesectionIII.5.3.

4.8. Second-line ART regimensTheentireregimenshouldbechangedfromafirst-linetoasecond-linecombinationonlyintheeventofimmunologicalorclinicalfailureafter24weeksoftreatment.Thenewsecond-lineregi-menshouldincludeatleastthreenewdrugs,oneormoreofthemfromanewclass,inordertoincreasethelikelihoodoftreatmentsuccessandminimizetheriskofcross-resistance,anditshouldbebasedupondrugsthatretainactivityagainstthepatient’sviralstrain(seeTable5).

TheadvantagesofPI-basedregimensincludeprovenclinicalefficacyandwell-describedtoxicities.Becauseofthediminishedpotentialofalmostanysecond-linenucleosidecomponent,alow-dosedRTV-enhancedPI(PI/r)componentisrecommended.

Table 5. Second-line art for infants and children

First-line ART regimen at failurePreferred second-line ART regimen

NRTI/NNRTI components

+

PI componenta

2 NRTIsa + 1 NNRTIContainingABC+3TC+(+NVPorEFV) ZDV+ddIb LPV/rd

orSQV/re

orNFVf

ABC+3TC ZDV+ddIb

Triple NRTI(ZDV+3TC+ABC)

ddIb+EFVcorNVP

aContinuationof3TCinthesecondlinemaybeconsidered.bShouldnotbetakenonanemptystomach.cEFVisnotrecommendedforchildren<3yearsofageor<10kg,norshoulditbegiventosexuallyactivegirlswhoarenotusingadequatecontraception.dLPV/risavailableassolidorliquid.eSQV/rshouldnotbeusedinchildrenweighing<25kg.fUnboostedNFVmaybeusedwherenocoldchainisinplace,andshouldbetakenwithfood(ifotherPIsarenotavailable).

4.9. Strategies in the event of second-line treatment failureMultidrugresistanceinchildrenwhohavereceivedmultipleantiretroviralregimensisanincreas-ingprobleminpaediatrictreatmentindevelopedcountries.Limiteddataareavailableformakingrecommendationsabouttreatmentoptionsinthesecases.SuchdecisionsarecomplexandrequireconsultationwithanHIVspecialist;referthechildandthecaregivertothetertiary-levelhospitalasindicated.

Possiblestrategiesinclude:• additionorsubstitutionofnewdrugs(suchasenfurvirtide/T20)• strategicrecyclingofdrugs• structuredtreatmentinterruptions• continuationofcurrenttreatmentuntiladditionaldrugsbecomeavailable.

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5. Monitoring children with HIVChildrenwithHIVshouldbemonitoredregularlyinordertoadjustcasemanagementstrategyandtreatmentplans.SuchmonitoringshouldcoverthehealthconditionsofthosenoteligibleforARTaswellasthosewhoareundertreatment.

5.1. Routine monitoring of patients before ARTThemainreasonsformonitoringHIV-infectedchildrenaretoidentifythepropertimeforinitiationofART,topreparethepatientandcaregiverforARTandtoprevent,detectandtreatcommonHIVcomplications.• ClinicalevaluationofinfantsandchildrennotyeteligibleforARTshouldbeperformedevery

3–6months.• Thesameparametersthatwereusedinthebaselineevaluationshouldcontinuetobemonitored.

Allchildrenshouldbeplottedonagrowthchart,asgrowthfailureisoneof thecommonestAIDS-definingsymptomsinpaediatricHIV.

• ClinicalevaluationandCD4measurementscanbeperformedmorefrequentlyastheclinicalorimmunologicalthresholdforinitiatingARTapproaches(seeTable2).

• Evaluationandnutritionalsupportshouldbeprovidedduringeachcontactwithchildrenandcaregivers,preferablyeverymonth.

5.2. Routine monitoring of patients on HAARTChildren’sresponsestoARTshouldbemonitoredregularly,includingclinical,laboratoryandad-herencemonitoring.

5.2.1. Clinical monitoring

Clinicalmonitoringshouldbeperformedeverythreemonths,focusingonimportantsignsofARTresponse,including:• growth,especiallyinchildrenwhohavebeenfailingtogrow;• neurologicalsymptomsanddevelopmentinchildrenwhohaveencephalopathyorhavebeen

lateinreachingdevelopmentalmilestones;and• typeandfrequencyofopportunisticinfections(bacterialinfections,thrush,etc.).

5.2.2. Laboratory monitoring

• CD4valuesshouldbemeasuredeverythreemonths,ormoreoftenifclinicallyindicated.• LaboratorymonitoringofARVtoxicityandcomorbiditiesshouldlargelybedirectedbyclinical

symptoms.

5.3. Immune reconstitution inflammatory syndromeIRIShasbeenobservedinadultsandlessfrequentlyinchildrenstartingART,particularlythosewithverylowCD4values(49–54).Symptomsaresimilartothoseseeninopportunisticinfections.TheyusuallyoccurwithinthefirstthreemonthsafterthestartofpotentART(55),concurrentwitharapidriseinCD4values.It isalsopossiblethat immunologicalreconstitutionmayleadtothedevelopmentofatypicalpresentationsofsomeopportunisticinfections.

5.4. Monitoring ARV toxicityDistinguishingcomplicationsofHIVdiseasefromtoxicitysecondarytoARVsissometimesdif-ficult.AlternativeexplanationsforapparentARVtoxicitycanincludeaconcurrentinfection(suchasviralhepatitisinfectioninachildwithhepatitissymptoms),orareactiontoaconcurrentnon-

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ARVdrug(suchasisoniazid-inducedhepatitisinachildonTBtreatmentorcotrimoxazole-inducedrashinachildreceivingpreventivetherapy).Suchnon-ARV-relatedadverseeventsdonotneces-sitateachangeinARVs.Drug-relatedadverseeventsmaybeacute(occurringsoonafterthedrugisadministered),subacute(occurringwithinoneor twodays)or late (occurringafterprolongedadministration).4

Mosttoxicitiesarelesscommoninchildrenthaninadults(forexample,NVP-relatedsymptomatichepatotoxicityisrareinchildren).Adverseeventscanvaryinseverityfrommildtosevereandlife-threatening.TakethefollowingstepswhenmanagingARVtoxicity:• Determinetheseriousnessofthetoxicity.• EstablishwhethertoxicityisduetoanARVoraconcurrentnon-ARVmedication.• Considerotherdiseaseprocesses(forexample,viralhepatitisinARVpatientswithjaundice),

sincenotallproblemsthatariseduringtreatmentareduetoARVs.• Managetheadverseeventaccordingtoitsseverity. ° Incaseofseverelife-threateningreactions,immediatelydiscontinueallARVs,managethe

medicaleventandthenreintroducethesameARVsinamodifiedregimen,substitutingfortheoffendingdrugwhenthepatientstabilized.Suchreactionsareveryrareandareusuallyonlyseenwithfulminanthyperlactaemia.

° Incaseofseverereactions,substitutefortheoffendingdrugwithoutstoppingART.Severereactionsarealsorare,andtheymostcommonlyoccurwhenachilddevelopslipoatrophyorneuropathyfromprolongedd4Tuse.

° Incaseofmoderatereactions,considercontinuationofARTaslongasfeasible;ifthepatientdoesnotimproveonsymptomatictreatment,considersingledrugsubstitutions.

° Mildreactionsmaybebothersomebutdonotrequirechangesintreatment.• For mild and moderate reactions, stress the importance of maintaining adherence despite

toxicity.• Toreiterate,iflife-threateningtoxicitydevelops,allARVsshouldbestoppeduntilthepatient’s

conditionisstabilized.

Several distinct types of adverse effects commonwith certainARVsor drug classes havebeenidentified,including:• adversehaematologicalevents(anaemia,neutropeniaand,morerarely,thrombocytopenia)from

drug-inducedbone-marrowsuppression,mostcommonlyduetoZDVtreatment;• mitochondrialdysfunction,primarilyseenwiththeNRTIdrugs,includinglacticacidosis,he-

patictoxicity,pancreatitisandperipheralneuropathy;5

• lipodystrophyandmetabolicabnormalities,primarilyseenwithd4Tandritonavir-boostedPIs,aswellaswithcertainotherNRTIs;6and

• allergic reactionssuchas skin rashesandhypersensitivity reactions,morecommonwith theNNRTIsbutalsoseenwithcertainNRTIs,suchasABC.

4BriefdetailsoftoxicityforspecificdrugscanbefoundontheChildren’sHIVAssociationwebsite(http://www.bhiva.org/chiva)undertherelevantname.5NRTIsdifferintheirabilitytoaffectmitochondrialfunction,withd4ThavinggreatertoxicitythanZDV,and3TCorABChavingless.6Abnormalitiesincludefatmaldistribution,particularlyperipherallipoatrophyassociatedwithd4TandZDV,andbodyhabituschanges;hyperlipidaemia;hyperglycaemia,insulinresistanceanddiabetesmellitus;andosteopenia,osteoporosisandosteo-necrosis.

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5.4.1. Clinical signs of ARV toxicity and its management

Table 6. Signs of arV toxicity and its management

Clinical manifestations Laboratory abnormalities Toxicity management

Acute serious adverse reactions

Acute symptomatic hepatitis (NNRTIs – particularly NVP, more rarely EFV – NRTIs and PIs)

JaundiceLiverenlargementGastrointestinalsymptomsFatigue,anorexiaHypersensitivity(rash,fever,sys-temicsymptoms),usuallywithin6–8weeksLacticacidosis(seebelow)ifsec-ondarytoanNRTI

ElevatedaminotransferaselevelsElevatedbilirubin

DiscontinueallARVsuntilsymptomsresolve.Monitoraminotransferaseandbilirubinlevels.IfthepatientisonNVP,itshouldbedis-continuedandnotre-administered.Oncesymptomsresolve,either:• changetoanalternativeARV(required

forNVPregimens);or• restarttheARTregimenwithclose

observation;ifsymptomsrecur,substi-tuteanalternativeARV(seeTable7).

Acute pancreatitis (NRTIs, particularly d4T and ddI, more rarely 3TC)

SeverenauseaandvomitingSevereabdominalpainLacticacidosis(seebelow)

ElevatedpancreaticamylaseElevatedlipase

DiscontinueallARVsuntilsymptomsresolve.Monitorserumpancreaticamylaseandlipase.Oncesymptomsresolve,restartARTwithanalternativeNRTI,preferablywithoutpancreatictoxicity(seeTable7).

Hypersensitivity reaction (ABC, NVP)

ABC:acuteonsetofrespiratoryandgastrointestinalsymptoms,includ-ingfever,fatigue,myalgia,nausea,vomiting,diarrhoea,abdominalpain,pharyngitis,cough,dyspnoea;rash(usuallymild);progressiveworsen-ingofsymptomssoonafterreceiv-ingABCdose,usuallywithin6–8weeksNVP:systemicsymptomsoffever,myalgia,arthralgia,hepatitis,withorwithoutrashc

ElevatedaminotransferaselevelsElevatedeosinophilcount

ImmediatelydiscontinueallARVsuntilsymptomsresolve.NVPandABCshouldnotbere-adminis-teredtothepatientinfuture.Oncesymptomsresolve,restartARTwithanalternativeARVforABCorNVP(seeTable7).

Lactic acidosis (NRTIs, particularly d4T)

GeneralizedfatigueandweaknessGastrointestinalsymptoms(nausea,vomiting,diarrhoea,abdominalpain,hepatomegaly,anorexiaand/orsuddenunexplainedweightloss)Hepatitisorpancreatitis(seeabove)Respiratoryfeatures(tachypnoeaanddyspnoea)Neurologicalsymptoms(includingmotorweakness)

IncreasedaniongapLacticacidosis(symptomsmaycontinueorworsendespitedis-continuingART)ElevatedaminotransferaselevelsElevatedCPKElevatedLDH

DiscontinueallARVsuntilsymptomsresolve.Oncesymptomsresolve,restartARTwithanalternativeNRTIthathaslowermitochon-drialtoxicityrisk(e.g.ABCorZDV)(seeTable7).

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Clinical manifestations Laboratory abnormalities Toxicity management

Severe rash/Stevens–Johnson syndrome (NNRTIs, particularly NVP, less commonly EFV)

Rashduringfirst6–8weeksMild-to-moderate rash:erythema-tous,maculopapular,confluent,mostoftenonthebodyandarms;nosystemicsymptomsSevere rash:extensiverashwithmoistdesquamation,angio-oedemaorserumsickness-likereaction;orarashwithconstitutionalfindingssuchasfever,orallesions,blistering,facialoedema,conjunctivitisLife-threateningStevens–Johnsonsyndromeortoxicepidermalnecrolysis

Elevatedaminotransferaselevels

Formildormoderaterash,continueARTwithoutinterruptionbutundercloseobser-vation.Forsevereorlife-threateningrash,discon-tinueallARVsuntilsymptomsresolve.NVPshouldnotbereadministeredtothepatient.Oncesymptomsresolve,restartARTwithanalternativeARVforNVP(seeTable7below).(Note:mostexpertswouldnotchangetoanotherNNRTIifthepatientexperiencedsevereorlife-threateningSte-vens–JohnsonsyndromefromNVP.)

Severe life-threatening anaemia (ZDV)Severepallor,tachycardiaSignificantfatigueCongestiveheartfailure

Lowhaemoglobin Ifrefractorytosymptomatictreatment(e.g.transfusion),discontinueZDVonlyandsubstituteanotherNRTI(seeTable7below).

Severe neutropenia (ZDV)Sepsis/infection Lowneutrophilcount Ifrefractorytosymptomatictreatment

(e.g.transfusion),discontinueZDVonlyandsubstituteanotherNRTI(seeTable7below).

Chronic late serious adverse reactions

Lipodystrophy/metabolic syndrome (d4T, PIs)

Fataccumulationand/orlossindistinctregionsofthebody:• increasedfataroundtheabdo-

men,buffalohump,breasthypertrophy;and

• fatlossfromlimbs,buttocksandface

Insulinresistance,includingdiabetesmellitusPotentialriskforlatercoronaryarterydisease

HypertriglyceridaemiaHypercholesterolaemiaLowHDLlevelsHyperglycaemia

Donotprescribed4T.SubstitutionofanNNRTIforaPImaydecreaseserumlipidabnormalities.

Severe peripheral neuropathy (d4T, ddI; more rarely 3TC)

Pain,tingling,numbnessofhandsorfeet;refusaltowalkDistalsensorylossMildmuscleweaknessandareflexia

None StoponlythesuspectedNRTIandsubsti-tuteanNRTInotassociatedwithneurotox-icity(seeTable7).Symptomsmaytakeseveralweekstoresolve.

Source:WHO(30)

5.4.2. ARV substitution in first-line regimens due to toxicity

GiventhelimitednumberofARVoptions,drugsubstitutionsshouldbelimitedtosituationswheretoxicityissevereorlife-threatening(seeTable6).SubstitutionwithPIsbecauseoftoxicityshouldbeavoidedifpossible.

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Table 7. arV substitution options in first-line art

First-line ARV Most frequent significant toxicities Suggested first-line

ARV drug substitution

ABC Hypersensitivityreaction ZDVZDV Severeanaemiaorneutropeniaa ABC

Lacticacidosis ABCSeveregastrointestinalintoleranceb ABC

EFV Persistentandseverecentralnervoussystemtoxicityc NVP

Teratogenicity(avoidinadolescentgirlsinfirst-trimesterpregnancyorwhohavechildbearingpotentialbutdonotreceiveadequatecontracep-tion)

NVP Acutesymptomatichepatitisd EFVe

Hypersensitivityreaction NRTIsubstitutionpreferred,givingatripleNRTI(Note:maybelesspotent);orPIsubstitution(Note:prematurestartofsec-ond-lineARV)

Severeorlife-threateningrash(Stevens–Johnsonsyndrome)f

aDefinedasasevere,possiblylife-threateninghaematologicalabnormalitythatisrefractorytosupportivetherapy.bDefinedasasevere,refractorygastrointestinalintolerancethatpreventsingestionoftheARVregimen.cDefinedasseverecentralnervoussystemtoxicitysuchaspersistenthallucinationsorpsychosis.dSymptomaticNVP-associatedhepatictoxicityisveryrareinHIV-infectedchildrenpriortoadolescence.eEFVisnotcurrentlyrecommendedforchildren<3yearsofageor<10kg,andshouldnotbegiventopost-pubertaladolescentgirlswhoareeitherinthefirsttrimesterofpregnancyoraresexuallyactivewithoutadequatecontraception.fSevererashisdefinedeitherasanextensiverashwithdesquamation,angio-oedemaorserumsickness-likereactions,orarashwithconstitutionalfindingssuchasfever,orallesions,blistering,facialoedemaorconjunctivitis.Stevens–Johnsonsyndromecanbelife-threatening.Forlife-threateningrash,mostclinicianswouldnotsubstituteEFVduetothepossibilityofNNRTI-classtoxicity.

5.5. Monitoring adherence As there isevidence thatadherence toHAARTpredicts thevirologicalandclinical response totreatment(23, 43, 44),monitoringitisessential.Monitoringadherenceshouldbeseenasateamresponsibilityofthepatient,caregiverandhealthcareworkers.Interventionstrategiesinclude:• It is important tomonitorandassessadherenceateachvisit, forexamplebyusingasimple

questionnaire,andbetweenvisitsbytelephoneorletterasneeded• usingpillboxes,reminders,alarms,pagersortimers• usingpatienteducationaids,includingpicturesandcalendars• patientsupportgroupsorone-on-onecounselling• directlyobservedtreatment(DOT)• adherencechecklistforcaregivers• discussingpotentialadherenceconstraintswithcaregiversWhenchildrenare8–10yearsoldatdiagnosis,adherencemayimproveincontrasttoyoungerchil-dren.Theage,maturityandsocialcircumstancesofthechildrenshouldbetakenintoconsideration,andcommunicationshouldoccurinalanguageandataleveltheycanunderstand.

Children’ssupportgroupscanbehelpful,inwhichchildrencometothehospitalandplay(educa-tional)gamestogether.TheylearntheyarenottheonlyoneswithHIV,whiletheircaregiversalsohavetheopportunitytotalkwitheachother.

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5.6. Nutritional and growth monitoring Systematicevaluationofnutritionalstatusandrelatedsymptomsiscriticaltoearlyidentifica-tionofmalnutritionandpoorgrowth,anditshouldbepartofroutineclinicalmonitoringofHIV-infectedinfantsandchildren.• Forinfants,nutritionalevaluationshouldoccurmonthlyandotherchildreneverythreemonths, andincludes: ° modeoffeeding7

° frequency,durationorquantitytaken ° adequacyofsupply ° bowelandurinehabits ° reportedproblems(56).• Childrenshouldbemeasuredandweighedateachvisitassessment: ° usethesamescaleateachvisit ° measurelengthofbabiessupine ° measurelengthofchildren>2yearsstanding ° measureheadcircumferencetoobtaingreatest ° genderandagespecificityshouldbetakenintoconsideration ° plotgrowthparametersonchart.• Ifthechildrequiresparticularattentionduetogrowthproblemsorspecialnutritionalrequire mentsitshouldbeperformedmoreoften(56).

5.7. Developmental assessment Itisimportanttoassessandcontinuetomonitorthedevelopmentofcognitive,motor,languageandsocialskillsofinfantsandyoungchildrenasasignificantproportionofthemshowearlyandmarkeddelaysintheseareasthatmaybeimportantearlyindicatorsofHIVdiseaseprogression(57, 58).• Adevelopmentalassessmentshouldbeconductedateachvisit.• Theassessmentshouldincludecognitive,motor,languageandsocialskills.• Discusstheinfant’smilestonesandverifythatthechildisdevelopingappropriatelyforage.• Usethedevelopmentalchicklistorobservetheinfantduringtheexamination(seeAnnex4)

(56).

Theprimaryaimisearlydetectionofdevelopmentalweaknessesinordertofacilitateinterventiontopreventand/orreducetheimpactofsevereproblems.

7TheWHORegionalOfficeforEuroperecommendsinfantformulaefeeding;whenthisisnotavailableexclusivebreast-feedingisanalternative.

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IV.Preventionandmanagementofmajoropportunisticinfections

TheoptimalmanagementofchildrenwithHIVinfectionrequiresattendingtomorethanjustART.ChildrenwithverylowCD4countsfortheiragearethemostatriskforOIs.Whenconsideringprophylactictreatmentinanewlypresentingandseverelyimmunosuppressedchild,thefirstprior-ityistostarteffectiveARTtorestoretheimmuneresponse.ForchildrenwhohavefailedmultipleARTregimesandhaveverylowCD4counts,whetherornottheyarecurrentlyonART,appropriateOIprophylaxisisextremelyimportant.8

1. Tuberculosis Tuberculosis(TB)representsasignificantthreattochildhealth,andHIVinfectionincreasessus-ceptibilitytoinfectionwithM. tuberculosisandtheriskofrapidprogressiontoTBdisease.Pleaserefer toProtocol 4,Management of tuberculosis and HIV coinfection, for recommendations re-gardingidentificationofTB/HIVininfantsandchildren,andclinicalmanagementofTB/HIVinchildren.

2. Disseminated mycobaceteriosis other than TB (DMOT)DMOTisassociatedwithsevereimmunosuppressionandaCD4count<50cells/mm3.NinetypercentofcasesareduetoMycobacterium aviumcomplex(MAC).Mediansurvivalforchildrenissixmonthsfromdiagnosis.SuchcasesshouldbediscussedwithanHIVpaediatrician.

2.1. Prophylaxis DMOTcanbepreventedbygivingallchildrenwithaCD4count<50azithromycin20mg/kgasasingleweeklydose(toamaximumof600mg).

2.2. DiagnosisClinicalfeaturesusuallyincludeprolongedfever,bonemarrowsuppression,weightlossandchron-icgastrointestinalsymptoms. InpatientswithDMOT,MACmaybe isolatedfromthe lungs,oracid-fastbacilli(AFB)maybedetectedinthestoolsorbonemarrow.Radiologicalpresentationcanoccurasenlargedhilarlymphnodes.

2.3. TreatmentTreatmentinvolvesacomplexmultidrugregimeofciprofloxacin,rifabutinandclarithromycinandisvalidforallages.Rifabutinisnotavailableinaliquidformulation,butasuspension(10mg/mlincherryorsimplesyrup)canbeformulatedfromthecontentsofcapsules(60).

If theclinicalpresentationissuspectedthenmycobacterialbloodculturesshouldbetakenusingthespecialbottlesavailablefrommicrobiology.Mycobacterialstoolculturesshouldalsobetaken.TreatmentforDMOTisshowninTable8.

Table 8. treatment of dmOt

Antimicrobial Agent Dose Frequency Route Duration

ciprofloxacin+rifabutin+clarithromycin*

30mg/kg

10–20mg/kg

7.5mg/kg

BID(twicedaily)(maxdose750mg)

OD(oncedaily)(maxdose300mg/day)

BID(maxdose500mg)

PO(orally)

PO

PO

6months

*Ifclarithromycinisnotavailable,itcanbesubstitutedwithethambutol,15mg/kgOD,PO.

8MuchofthissectionisbasedonortakendirectlyfromTreating Opportunistic Infections In HIV-Infected Children Guidelines for the Children’s HIV Association (CHIVA) (59),withthepermissionoftheauthorsandCHIVA.Moredetailsofthepreven-tionandmanagementofopportunisticinfectionsininfantsandchildrencanbefoundontheChildren’sHIVAssociationweb-site(http://www.bhiva.org/chiva/protocols/supportdocs/CHIVA-presubmissionAug06.pdf).

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Beawareofpossiblecomplexdruginteractions,especiallywithrifabutin.Forpossibledruginterac-tionsandmanagementstrategiespleaserefertowww.druginteraction.org.

3. Pneumocystis jirovecii pneumonia PCPisoneofthemostcommoncategoriesofHIV-associatedOIs,occurringinabout40–50%ofchildrenreportedtohaveHIVinfection.IthasalsobeenidentifiedastheleadingcauseofdeathininfantswithHIVinfectionandaccountsfor50–60%ofAIDSdiagnosesininfants(61, 62).PCPismostcommoninchildrenunderoneyearold(72%ofchildrenpresentingwithPCP)(63),forwhomchemoprophylaxisofPCPisrecommended.

3.1. ProphylaxisProphylaxis with cotrimoxazole (trimethoprim-sulfamethoxazole, or TMP-SMZ) (see Table 9 )isrecommendedfor:• allHIV-exposedinfants,startingat4–6weeksofageandcontinuinguntilHIVinfectioncanbe

excludedbyvirologicaltesting(youngerthan18monthsofageinnon-breastfeedinginfants)orserologicaltesting(18monthsandolder);and

• allchildrenunderoneyearoldwithdocumentedHIVinfection,regardlessofsymptomsorCD4percentage.

Onceinitiated,prophylaxisshouldbecontinueduntilage5,whendiscontinuingmaybeconsideredinaccordancewiththerecommendationsforadultsandadolescents.

Table 9. cotrimoxazole (tmP-SmZ) formulations and dosage for HiV-infected

Recommended once-daily dosagea

Suspension(5mlsyrup,40/200mg)

Paediatric tablet(20/100mg)

Single-strength adult tablet(80/400mg)

Double-strength adult tablet(160/800mg)

<6 months20/100mg

2.5ml 1tablet ¼tablet,possiblymixedwithfeedingb

–

6 months–5 years40/200mg

5mlc 2tablets ½tablet –

6–14 years80/400mg

10mlc 4tablets 1tablet ½tablet

>14 years160/800mg

– – 2tablets 1tablet

aSomecountriesmayuseweightbandstodeterminedosage.ThefollowingtableisfromtheCHAPtrial:

Age Weight

<6months <5kg

6months–5years 5–15kg

6–14years 15–30kg

>14years >30kgbSplittingtabletsintoquartersisnotconsideredbestpractice.Itshouldbedoneonlyifsyrupsarenotavailable.cChildrenoftheseages(6months–14years)maybeabletoswallowcrushedtablets.Source:adaptedfromWHO(64, 65).

AftersuccessfullytreatinganacuteepisodeofPCP,itisnecessarytocontinuesecondaryprophy-laxiswithcotrimoxazoleonalong-termbasistopreventrecurrence.Itmaybediscontinuedwhenthepatient’sCD4countremainsstableforatleastthreemonths.

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3.2. DiagnosisTheclinicalfeaturesofPCParetachypnoea,dyspnoea,cough,hypoxiaandlow-gradefever.Theonsetmaybeinsidiousoveroneortwoweekswithslowlyincreasingtachypnoea.Coughingisnotusuallyprominentuntilthefullclinicalpicturedevelopswithseveredyspnoea.Physicalfindingsareusuallylimitedtofinecrepitations.Feverisoftenlowgrade.Arapidlyprogressivecourseofdiseaseleadingtorespiratoryfailureinafewdayshasalsobeendescribed.TheclassicchestX-raymaybenormalorhyperinflatedearlyinthedisease,butthereisusuallyrapiddevelopmentofcompleteopacificationwithairbronchograms.Thealveolarinfiltratesprogressperipherallywithlateapicalsparingandsmallpleuraleffusionsreported.Occasionallybullae,cystsorpneumothoraxmaybeseen.

In infants,bronchoscopywithbronchoalveolar lavage(BAL) isnowtheoptimalmethodfordi-agnosingPCP.BALcanbedoneusingan8Fnasogastricfeedingtubeinintubatedchildrenwhomaynottoleratebronchoscopy.IfBALcannotbeperformedimmediately,thenstartcotrimoxazoletreatmentfirst(positiveresultscanbeobtainedupto48hoursafterstartingtreatment).Themicro-biologylaboratoryshouldbeinformedpriortoBAL,asitisveryimportanttomakeadefinitivediagnosisevenaftercommencingtreatment.

3.3. TreatmentSeeTable9abovefortherecommendedinitialtreatmentofPCP.• Aftertheacutepneumonitishasresolved,childrenwithmild-to-moderatediseasewhodonot

havemalabsorptionordiarrhoeacanreceivetreatmentwiththedoseofTMP-SMZ60mg/kgevery12hours,IV,oncethechildisonoralfeeding(aroundthesecondweekoftreatment)ad-ministertreatmentPOforatotalofa21-daycourse.

• If there is failure to respond tocotrimoxazole,or anallergic reaction, second-line treatmentshouldbeundertaken(seeTable10).

• Incaseoffailuretorespondtocotrimoxazole,repeatedBALorlungbiopsyshouldbeconsid-ered.

• Cytomegalovirus (CMV) is frequently found in BAL with PCP infection, but ganciclovirshouldonlybeusedforchildrenwithPCPandCMViftheyarenotrespondingtostandardPCPtherapy.

• IncaseofamoderateandseverePCP,oralprednisolonemightbeanoption:2mg/kg1week,1mg/kg1week,0.5mg/kg1week.

Table 10. Second-line treatment

Antimicrobial agenta Dose Frequency Route Durationpentamidineisethionate 4mg/kg/day OD Pentamidineisethi-

onateslowinfusionIVfor14–21days

14–21days

or:dapsone 2mg/kg(max.100mg) OD PO 21days

aAtovoquoneorclindamycinmightalsobeachoice,howeveronlylimiteddataexistsregardingitsuseinchildren.

4. Bacterial infections (non-mycobacterial)SeriousbacterialinfectionsareverycommonamongHIV-positivechildren.Thefrequencyofbac-terialinfectionincreaseswithHIVdiseaseprogressionandimmunosuppression.Thecommonestorganismsareencapsulated Streptococcus pneumoniae and Haemophilus influenzae. Staphylococ-cusaureusandgram-negativeinfections,especiallyPseudomonas aeruginosa,areseenmorecom-monlyinchildrenwithsevereHIVinfection(63).

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4.1. DiagnosisTheclinicalpresentationofacutebacterialpneumoniainchildrenwithearlyHIVinfectionissimilartothatinnon-infectedchildren:thecommonestclinicallydiagnosedinfectionisacutepneumoniaandprimarysepticaemia.TheclinicalsignsmaybelessobviousinchildrenwithHIV.Itisalwaysimportanttoobtainbloodcultures.Earinfectionsandthroatinfectionsareverycommon.Sinusitisshouldbeparticularlysoughtfor,eitherbyclinicalsignsorsinusX-rays.

4.2. TreatmentAchildwithclinicalevidenceofanacute lower respiratory tract infection (fever,cough, raisedrespiratory rate, chest signs orCXR changes) should be treated promptly and empiricallywithbroad-spectrumantibiotics(oralco-amoxiclavorIVceftriaxone).Thechoiceoforalorintravenousantibioticsdependsonthepatient’sclinicalcondition.Ifthereisapoorresponsetotreatmentaddazithromycin(10mg/kgODfor5days)andconsiderBAL.Generally,treatmentregimesshouldbelong(10–14days).

5. Toxoplasmosis Toxoplasma encephalitis shouldbeconsidered inallHIV-infectedchildrenwithnewneurologicfindings.Althoughfocalfindingsaremoretypical,theinitialpresentationcanbevariableandre-flectdiffusecentralnervoussystem(CNS)disease.

5.1. ProphylaxisPCPprophylaxisalsoprovidesprophylaxisagainsttoxoplasmosis.Atovoquonemayalsoprovideprotection. Severely immunosuppressed children (withCD4 cell count <100/mm3)who are notreceivingTMP-SMZoratovoquoneandare found tobeseropositive forToxoplasma shouldbeadministeredprophylaxisforbothPCPandtoxoplasmosis(i.e.dapsonepluspyrimethamine)(seeTable11).

IndicationforprophylaxispreventioninTable11isIgGantibody-positiveforToxoplasmaandse-vereimmunosuppression(CD4<15%).

Table 11. Prophylaxis to prevent first episode of toxoplasmosis

Antimicrobial agent Dose Frequency Route DurationFirst line treatmentcotrimoxazole 960mg/m2 OD PO UntilCD4

>200mm3

Alternativedapsone+pyrimethamine+folicacid

Or

atovoquone

2mg/kg(max25mg)

1mg/kg

5mg

age1–3months30mg/kg

age4–24months45mg/kg

age>24months30mg/kg

OD

OD

Every3days

OD

OD

OD

PO

PO

PO

PO

PO

PO

UntilCD4>200mm3

UntilCD4>200mm3

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5.2. DiagnosisApresumptivediagnosisofToxoplasmaencephalitisisbasedonclinicalsymptoms,serologicev-idence of infection, and the presence of a space-occupying lesion on imaging studies. Clinicalsymptomsincludemotorandspeechdisturbances,oftenaccompaniedbyheadache,alteredmentalstatus,andfever.Childrencanalsopresentwithseizures,cranialnerveabnormalities,visualfielddefects,sensorydisturbances,cerebellardysfunction,meningismusandmovementdisorders(66).ManifestationsofextracerebraltoxoplasmosisinHIV-infectedchildrenincludeoculartoxoplasmo-sis,whichoccursmostofteninassociationwithToxoplasmaencephalitisnecessitatingneurologicexamination.Patientswithchorioretinitispresentwithblurredvision,painorphotophobia(67).

ChildrenwhoareinfectedlatentlywithToxoplasma gondiihavevariableIgGtitresandrarelypos-sessIgMantibody.AlthoughseroconversionandfourfoldincreaseinIgGantibodytitersmayoccur,theabilitytodiagnoseactivediseaseiscommonlyimpairedbyimmunosuppression.IgMantibod-iestypicallydisappearafewmonthsafterinfectionbutcanremainelevatedformorethan1yearconfoundingthedifferentiationofacuteandremoteinfection(68).

AdditionalinvestigationstosupportthediagnosisofToxoplasmaencephalitisinclude(whereavail-able)CTscanningofthebrainthatmightindicatemultiple,bilateral,hypodense,focalring-enhanc-inglesionsespeciallyinthebasalgangliaandcerebralcorticomedullaryjunctionin70-80%ofpa-tients(69).Magneticresonanceimagingismoresensitiveandwillconfirmbasalganglialesionsinmostpatients(70).AlthoughtoxoplasmicencephalitiscanoccasionallycauseasinglebrainlesiononMRI,suchafindingsuggestsanalternativediagnosis(primarilyCNSlymphomaandtubercu-loma)(71).

DefinitivediagnosisofToxoplasmaencephalitisrequireshistologicconfirmationbybrainbiopsy,andcanbeconsideredwhenearlyneurologicdeteriorationispresentdespiteempirictreatmentorinchildrenwhofailtorespondtoanti-Toxoplasmatherapyafter10–14days.Iflumbarpunctureisnotcontraindicated,PCRofCSFshouldalsobeconsidered.Oculartoxoplasmosisisdiagnosedonthebasisofobservationofcharacteristicretinallesionsinconjunctionwithserumspecificantibodies.

5.3. TreatmentAcuteinductiontherapyshouldbefollowedbychronicsuppressivetherapy(seeTable12).

Table 12. treatment of acquired toxoplasmosis: acute induction therapy

Antimicrobial agenta Dose Frequency Route Durationpyrimethaminethenpyrimethamine+sulphadiazine+Folicacid

2mg/kg/day(max:50mg)

1mg/kg(max:25mg)

25-50mg/kg(max:1.0-1.5g/dose)

10-25mg

OD

OD

QID(fourtimesdaily)

OD

PO

PO

PO

PO

3days

Atleast6weeks

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6. Fungal infections

6.1. Candidiasis

6.1.0.1. ProphylaxisImmunereconstitutionwithARTaccompaniedbyareductioninplasmaHIVviraemiaisthebestinterventiontoreducetherateofcandidacolonizationandclinicaldisease(72, 73).Otherusefulinterventionsincludegoodoralhygiene,avoidanceofunnecessaryantibioticsandsteroids,andspe-cificantifungalmedications.Continuousprophylacticanticandidatherapyisrarelyindicated,andmayresultintheemergenceofresistantandrefractoryinfections(74).Universalprimaryantifungalprophylaxisisthereforenotcurrentlyrecommendedandtheindicationsforsecondaryprophylaxisshouldbeindividualized.

6.1.1. Oropharyngeal candidiasis (OPC)

6.1.1.1. Diagnosis

OPChasvariableclinicalmanifestations:pseudomembranous (thrush), erythematous (atrophic),hyperplastic(hypertrophic)andangularcheilitis.Thrushisthemostclassicformoforalcandidiasis,appearingascreamywhitecurd-likepatcheswithinflamedunderlyingmucosaethatareexposedafterremovaloftheexudates.Itcanbefoundontheoropharyngealmucosae,palateandtonsils.ErythematousOPCmanifestsas flat erythematous lesionson themucosal surface.Hyperplasticcandidiasisiscomposedofraisedwhiteplaquesappearingonthelowersurfaceofthetongue,pal-ateandbuccalmucosaandcannotberemoved.Angularcheilitisoccursasred,fissuredlesionsinthecornersofthemouth.

DiagnosisoforalcandidiasiscanbemadebyaKOHpreparationandculturewithmicroscopicdemonstrationofbuddingyeastcellsinwetmountsorbiopsyspecimens.ForrecurrentorrefractoryOPC,cultureswithinvitrosusceptibilitytestingcanbeusedtoguideantifungaltreatment(75).

6.1.1.2. Treatment

Table 13. treatment options for children with oropharyngeal candidiasis

Antimicrobial agenta Dose Frequency Route DurationFirst line treatmentFluconazole 3–6mg/kg(max:400mg/day) OD PO 7–14daysAlternativeItraconazolecyclodextrinoralsolution

Or

AmphotericinBoralsuspension

2.5mg/kg(max:200mg/day)

1ml(100mg/ml)

BID

QID

PO

PO

7–14days

14days

6.1.2. Oesophageal candidiasis

6.1.2.1. Diagnosis

Thisconditioncanpresentwithodynophagia,dysphagiaorretrosternalpain,whichcanbesevereenoughtocausedehydrationandweight loss inchildren.Althoughoropharyngealcandidiasis iscommon,evidenceofitmaybeabsentamongchildrenwithoesophagealcandidiasis,particularlythosereceivingHAART.Unlikeinfectedadults,asubstantialnumberofchildrenwiththeconditionmayexperiencenauseaandvomiting.

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Oesophagealcandidiasishasaclassiccobblestoneappearanceonbariumswallow. In refractorysymptomaticcases,endoscopyshouldbeperformedtoruleoutothercausesofrefractoryoesophag-itis(HSV,CMV,MACandazole-resistantCandidaspecies).Endoscopiesmayshowanythingfroma few small white raised plaques to elevated confluent plaques with hyperaemia and extensiveulceration.

6.1.2.2. Treatment

Table 14. treatment options for children with oesophageal candidiasis

Antimicrobial agenta Dose Frequency Route DurationFirst line treatmentFluconazolethenFluconazole

6mg/kg/day

3–6mg/kg/day(max:400mg/day)

OD PO

PO

Day1

14–21days

AlternativeItraconazolecyclodextrinoralsolution

Or

AmphotericinB

paediatricdosage:2.5mg/kgor5.0mg/kg

0.3–0.5mg/kg/day

BID

OD

OD

PO

PO

IV

Atleast14–21days

Atleast7days

6.1.3. Candidaemia

6.1.3.1. Diagnosis

Anew-onsetfeverinanHIV-infectedchildwithadvanceddiseaseandacentralvenouscatheteristhemostcommonclinicalmanifestationofcandidaemia.Systemicfungaemiacanleadtoendog-enousendophthalmitis,andocularexaminationbyanophthalmologistmaybewarrantedamongchildrenwithcandidaemia.Diagnosisisbestmadewithbloodculturesusinglysis-centrifugationtechniques (76) or automatedbroth-based systems (77).When fungaemia is present, retinal ex-aminationforendophthalmitis,abdominalCATorultrasoundforhepaticorrenalinvolvement,andbonescansforclinicallysuspectedosteomyelitismaybeappropriate.

6.1.3.2. Treatment

PrimaryprophylaxisofcandidiasisinHIV-infectedinfants/childrenisnotindicated.

Table 15. treatment options for children with invasive candidiasis

Antimicrobial agenta Dose Frequency Route DurationFirst line treatmentFluconazoleIffailuretorespond:AmphotericinB

10mg/kg/day

250mcgincreasedby250mcgto1mg/kg

OD

ODoralternateday

IV

IV

21days

14days

AlternativeAmphotericinBlipidcomplex(Abelcet)

3mg/kg ODgivenovertwohours

IV 2–3weeks

417


7. Viral infections

7.1. Cytomegalovirus (CMV)

7.1.1. Prophylaxis

SeverelyimmunocompromisedchildrenwithHIV/CMVcoinfectionshouldhaveadilatedretinalexaminationperformedevery4–6months.Prophylaxisforchildrenhasnotbeenwellestablishedandused.ProphylaxiswithoralganciclovirorvalganciclovircanbeconsideredforHIV-infectedadolescentswhoareCMV-seropositivewithCD4cells countof<50cells/mm3 (seeTable16)butmustbebalancedwiththerisksof(val)ganciclovir-inducedneutropenia,anaemia,conflictingreportsofef-ficacy,lackofprovensurvivalbenefit,riskforemergenceofganciclovir-resistantCMV,andcost.NeitheraciclovirnorvalaciclovirshouldbeusedforCMVinfection.

Table 16. Prophylaxis for severely immunosuppressed adolescents (78)

Antimicrobial agent Dosea Frequency Route DurationValganciclovir

Maintenance phaseGanciclovir

900mg

900mg

BID

OD

PO

PO

21days

3–6monthsaTherearepresentlynopaediatricdosesavailable

Therearenodatatoguidedecisionsconcerningdiscontinuationofsecondaryprophylaxis(chronicmaintenancetherapy)inchildrenwithtreatedCMVdisease,butitisreasonabletoconsiderstop-pingwhentherearesustainedT-cellresponsestoART.

7.1.2. Diagnosis

InHIV-infectedchildren,CMVinfectionmaybedifficulttodifferentiatefromactiveCMVdisease.Becauseoftransplacentaltransferofantibodiesfrommothertochild,apositiveCMVantibodyas-sayinaninfantunder12monthsoldisindicativeofmaternalinfectionbutnotnecessarilyinfectionoftheinfant.Inachildolderthan12months,apositiveCMVantibodyassayindicatespreviousinfectionwithCMVbutnotnecessarilyactivedisease.Atanyage,apositiveCMVcultureisin-dicativeofinfection,butnotnecessarilyofdisease.CMVdiseaseisrareinHIV-infectedchildren,butitdoesoccurinchildrenwithsevereimmunosuppression,inwhomthecommonclinicalmani-festationsincludeCMVretinitis(withwhitefluffyexudates),hepatitisandcolitis.

CMVcanbeisolatedincellculturesfromperipheralbloodleukocytes,bodyfluidsandbodytissues.Usingcentrifuge-assistedshellvialcultureamplificationtechniques,CMVcanbedetectedwithin16–40hoursofcultureinoculation.Apositivebloodbuffy-coatcultureestablishesadiagnosisofCMVviraemiaandincreasesthelikelihoodthatCMVdiseaseorsymptomsarecausedbyCMV,becausechildrenwithpositivebloodculturesareathigherriskfordevelopingend-organdisease.

DifferentmethodshavebeenusedtodetectCMVantigenorDNAdirectlyandidentifypatientsatriskfordevelopmentofCMVdisease,includingdetectionofpp65antigenaemia,qualitativeandquantitativePCRandDNAhybridization.TheDNAassaysaremoresensitivethanbuffy-coatorurineculturesfordetectingCMVandcanbeusedtoidentifypatientsathigherriskfordevelopingclinicallyrecognizabledisease.CMVDNAdetectioninCSFbyDNAPCRishighlysensitiveforCMVdisease.QuantitativeDNAPCRcanbeusedasamarkerofriskfordiseaseandtomonitorresponsetotherapy(77).

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7.1.3. Treatment

Table 17. treatment of cmV infection

Antimicrobial agenta Dose Frequency Route DurationFirst line treatmentInduction phaseGanciclovir

Maintenance phaseGanciclovir

5mg/kg

5mg/kg

every12hours

OD

IV

IV

7days

2–3weeks

7.2. Varicella-zoster virus

7.2.1. Prophylaxis

Immunosuppressed HIV-infected children who are susceptible to varicella-zoster virus9 (VZV)shouldavoidexposuretopeoplewithchickenpoxorshingles.Fortheprophylaxisofchickenpox,HIV-infectedpatientssusceptibletoVZVshouldbeadministeredvaricella-zosterimmunoglobulin(VZIg)assoonaspossible, ideallywithin96hoursafteranyclosecontactwithchickenpoxorshingles.

TherearenodataontheeffectivenessofaciclovirforpreventingchickenpoxinHIV-infectedchil-drenoradults.

7.2.2. Diagnosis

ThediagnosisofVZVinfectionisoftensuspectedfromtheclinicalpresentationAgeneralizedse-verepruriticvesicularrashandfeverisdiagnostic.Lesionsappearfirstandaremostnumerousonthetrunk,neck,andface.Thevesiclescontainfluid,restonanerythematousbaseandulcerateanddrytoformcrustsandscabs.LesionsduringchronicVZVinfectionarevaricelliformatonsetbutmayevolveintonon-healing,necroticandcrustedulcersthatbecomehyperkeratotic(79).

Theclassicalclinicalpresentationofzoster(apainfullocalizedcutaneousvesiculareruptionalongoneormorecontiguousdermatomes)isdiagnostic.Lesionsevolveover1to2daystoformvesi-cles,pustules,andcrusts.InHIV-infectedpatients,zostermaybebullous,haemorrhagic,necrotic,andparticularlypainful.Blistersandcrustsusuallylast2–3weeks,althoughnecroticlesionsmaylastupto6weeksandhealwithseverescarring.ZosterinHIV-infectedchildrenmayalsopresentasanatypicalrashthatextendsbeyonddermatomalboundariesorisbilaterallydistributedorgen-eralizedorasmultipleepisodesofadisseminatedrashmoresimilarinappearancetochickenpoxthanzoster(80).

VaricellapneumonitisinHIV-infectedchildrenisassociatedwithseverepulmonarymanifestationsresulting in hypoxaemia and diffuse reticulo-nodular densities on radiography. Encephalitis oc-cursmorefrequentlywithzosterintheophthalmicdistribution,andcerebellarfindingsaretypical;prominentsymptomsincludeataxia,tremors,anddizziness.Cerebralinvolvementresultsinfever,headache,vomitingandlethargy(81).

Directimmunofluorescenceexpressedonthesurfaceofinfectedcellsfromscrapingsobtainedfromthebaseofskin,conjunctiva,ormucosallesionsallowVZVantigendetection,andisthediagnosticprocedureofchoice.DirectandindirectimmunofluorescenceorimmunoperoxidasemethodscanalsodetectantigeninVZV-infectedcellsintissuesectionsoflung,liver,brain,orotherorgans.

9SusceptiblepatientsarethosewhohavenohistoryofchickenpoxorshinglesorwhohavenodetectableVZVantibody.

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7.2.3. Treatment

Table 18. treatment of varicella-zoster infection

Infection Antimicrobial agenta Dose Frequency Route DurationVaricella Children with moderate or sever immune suppression, high fever or necrotic lesions

Acyclovir 10–20mg/kg TID(threetimesdaily)

IV 7daysafternonewlesions

Children with mild immune suppression and mild oral disease:Acyclovir 20mg/kg(max:

200mg/dose)QID PO 7daysafterno

newlesions

Zoster Children with severe immune suppression, trigeminal nerve involvement or extensive multider-matomal zoster IVAciclovir 10–20mg/kg TID IV 7–10daysChildren with mild immune suppression and mild oral diseaseAciclovir 20mg/kg(max:

200mg/dose)QID PO 7–10days

For patients not responding to acyclovira

Foscarnet 40–60mg/kg TID IV 7–10daysaValaciclovirisapprovedforuseinadultandadolescentswithzosteratadoseof1gramPOBID7–10days;dataondosinginchildrenislimited.

7.3. Herpes simplex virus (HSV)

7.3.1. Prophylaxis

HIV-infectedchildrenwithsevereoralrecurrences(morethan3–6severeepisodesayear)orprevi-ousdisseminateddiseasemaybenefitfromprophylaxiswithoralacyclovir(82).

7.3.2. Diagnosis

NeonatalHSVcanappearasdisseminatedmulti-organdisease(occurringinapproximately25%ofneonateswithHSVinfection),localizeddiseaseoftheCNS(approximately35%ofinfectedne-onates)orlocalizeddiseaseoftheskin,eyesandmouth(approximately40%ofinfectedneonates)(83).Vesicularrashispresentinapproximately80%ofchildrenwithlocalizedskin,eyeormouthdisease,butonlyinapproximately60%ofchildrenwithCNSordisseminateddisease(84, 85).

Outsideoftheneonatalperiod,themostcommonappearanceofHSVinfectioninchildrenisoro-labialdisease.Fever,irritability,tendersubmandibularlymphadenopathyandsuperficial,painfululcersinthegingivalandoralmucosaeandperioralareacharacterizeprimaryHSVgingivostoma-titis.HIV-infectedchildrenwhoexperienceprimaryinfectionwhentheyareimmunocompromisedcanhave severe local lesionsor,more rarely,disseminatedHSVwithvisceral involvementandgeneralizedskinlesionswithprimaryinfection.Othersitesofinvolvementamongseverelyimmu-nocompromisedHIV-infectedchildrenincludetheoesophagus,CNSandgenitalsanddisseminateddiseaseintheliver,adrenals,lungs,kidneys,spleenandbrain.

AmongchildrenwithsuspectedHSVencephalitis,detectionofHSVDNAbyPCRisthediagnos-tic testofchoice(86).CSFculturesforHSVareusuallynegative.DefinitivediagnosisofHSVoesophagitisrequiresendoscopywithbiopsy(histologicalevidenceofmultinucleatedgiantcellswithintranuclearviralinclusion)andculture.

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7.3.3. Treatment

Table 19. treatment of HSV disease

Condition Antimicrobial agenta

Dose Frequency Route Duration

Skin,eyeandmouthdisease

DisseminatedHSVdiseaseorencephalitis

SymptomaticHSVgingivostomatitis

Acyclovir 20mg/kg

20mg/kgor500mg/m2

5–10mg/kgOr20mg/kg

TID

TID

TID

TID

IV

IV

IV

PO

14days(63)

21days

7–14days

7–14daysAlciclovir-resistant HSV infection

Foscarnet 120mg/kg/day 2–3divideddosesover1–2hours(administerslowlyover2hoursornofasterthan1mg/kg/min.)

IV Untiltheinfectionresolves

AciclovirtherapyshouldnotbediscontinuedinneonateswithCNSdiseaseunlessarepeatCSFHSVDNAPCRassayisnegativeatday19–21oftreatment.

BecauseepisodesofHSVdiseasecanbetreatedsuccessfully,chronictherapywithaciclovirisnotrequiredafterlesionsresolve.However,peoplewithfrequentorsevererecurrencescanbeadmin-istereddailysuppressivetreatmentwithoralaciclovirorvalaciclovir.

421


V.PaediatricHIVpainmanagement

1. BackgroundPaininchildrenwithHIVAIDSisamultifactor,biologicallycomplexproblemassociatedwithdi-minishedqualityoflifeandincreasedmortality(87).Painelimination,painameliorationand(whenappropriate)palliativeadministrationofanalgesicsandsedativesareessentialaspectsofthecareofeveryHIV-infectedchild.

DespiteadvancesinthetreatmentandcontrolofHIVinfectioninchildren,painmaystillcompli-catemedicalmanagementanddiminishqualityoflifeforsomechildrenwithadvanceddisease.Be-causepaininthispopulationisoftencomplex,optimalmanagementwillbestbeachievedthroughthecoordinatedcollaborationofseveralspecialists,includinganaesthesiologists,painspecialists,socialworkers,nursingstaffandothers.

Patientswithpainaremorethanfivetimesmorelikelytodiethanthosewhodonotreportpain.PainisalsoassociatedwithlowerCD4cellpercentagesandmoresevereimmunosuppression(88).

2. Pain management strategiesPainmanagementinHIV-infectedchildrenshouldcombinepharmacologicalandnon-pharmaco-logicaltherapies.Thelatterinclude:• relaxationtechniquesandbehaviourmodification;• environmental management: play, music, scheduled medical and nursing interventions, and

structuredtimeforsleepandrest;• gentlehandlingandsupportivepositioning;• nutritionalsupport,adequatehydrationandelectrolytereplacement;• optimizedtissueperfusionandoxygenation;• transcutaneouselectricalnervestimulation(TENS),gentlemassage,whirlpoolbathsandphysi-

caltherapy;and• electricalorneedlestimulationofacupuncturemeridiansbyHIV-knowledgeablepractitioners

(88, 89).

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VI.Suggestedminimumdatatobecollectedattheclinicallevel

Thesuggestedminimumdatatobecollectedisimportantinthedevelopmentofkeyindicatorsonaccess todiagnosisand treatmentand theirsuccess.Such indicatorsassistmanagers indecisionmakingonwaystostrengthenandexpandtheseservicestoallwhoneedthem.

Thefollowingdatashouldbecollectedateachclinical facilityonaregularbasis (e.g.monthly,quarterlyorsemi-annually):• numberofinfants<18monthsofageborntoHIV-infectedmothers;• numberofinfants<18monthsofageborntoHIV-infectedmothersandhavehadPCRtesting;• numberofHIVdiagnosedinfectedinfants<18monthsofage;• numberofinfants≥18monthsofageborntoHIV-infectedmothers• numberofinfants≥18monthsofageborntoHIV-infectedmothersandhavehadonlyserologi-

calHIVtesting;• numberofHIV-infectedinfants≥18monthsofagediagnosedonlyserologically;• numberofHIV-infectedchildren(<15yearsold)seenforcarewhoareeligibleforHAART;• numberofHIV-infectedchildren(<15yearsold)seenforcareandreceivingfirst-lineHAART

regimen;• numberofHIV-infectedchildren(<15yearsold)onHAARTchangingfromfirst-lineHAART

tosecond-lineHAART;• numberofHIV-infectedchildren(<15yearsold) interruptingHAART, including the reasons

(e.g.death,toxicity/sideeffects,losstofollow-up,ARVsnotavailable,etc.);• numberofHIV-infectedchildrenwhodiedwhileonHAART,includingcauseofdeath(e.g.HIV/

AIDSrelatedmortalityornon-HIV/AIDSrelatedmortalitysuchasaccident,etc.);• numberofHIV-infectedchildrenwhodiedwithinfirst12monthsofinitiatingHAART;• numberofdeathamongallHIV infectedchildren includingcauseofdeath (e.g.HIV/AIDS

relatedmortalityornon-HIV/AIDSrelatedmortalitysuchasaccident,etc).

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Revised WHO clinical staging of HIV/AIDS for infants and children

(InterimEuropeanRegionversionforpeople<15yearsoldwithconfirmedlaboratoryevidenceofHIVinfection–

HIVantibodytestif≥18monthsold,virologicalorp24antigentestif<18months)

Clinical Stage 1• Asymptomatic• Persistentgeneralizedlymphadenopathy(PGL)

Clinical Stage 2 • Hepatosplenomegaly• Papularpruriticeruptions• Extensivemolluscumcontagiosum• Fungalnailinfections• Recurrentoralulcerations• Linealgingivalerythema(LGE)• Angularcheilitis• Parotidenlargement• Herpeszoster• Asymptomaticlymphocyticinterstitialpneumonitis(LIP)• Recurrentorchronicrespiratorytractinfections(otitismedia,otorrhoea,sinusitis)

Clinical Stage 3• Moderateunexplainedmalnutritionnotadequatelyrespondingtostandardtherapy• Unexplainedpersistentdiarrhoea(14daysormore)• Unexplainedpersistentfever(intermittentorconstant,forlongerthanonemonth)• Oralcandidiasis(excludingfirsttwomonthsoflife)• Oralhairyleukoplakia• Acutenecrotizingulcerativegingivitisorperiodontitis• Linealgingivalhyperplasia• Severerecurrentpresumedbacterialpneumonia• Extensiveandconfluentwarts• Giantdisfiguringmolluscum• ChronicHIV-associatedlungdisease,includingbronchiectasis• Symptomaticlymphocyticinterstitialpneumonitis(LIP)• Unexplainedanaemia(<8g/dl)and/orneutropenia(<500/mm3)• Unexplainedthrombocytopenia(<50000/mm3)formorethanonemonth

Clinical Stage 4• Unexplainedseverewastingorseveremalnutritionnotadequatelyrespondingtostandardtherapy• Recurrentseverepresumedbacterialinfections(e.g.empyema,pyomyositis,boneorjointinfectionormenin-

gitis,butnotpneumonia)• Chronicherpessimplexinfection(orolabialorcutaneousandofmorethanonemonth’sduration)• ExtrapulmonaryTB• Kaposisarcoma• Oesophagealcandidiasis• CNStoxoplasmosis(aftertheneonatalperiod)• HIVencephalopathy• CMVinfection(CMVretinitisorinfectionoforgansotherthanliver,spleenorlymphnodes;onsetatageone

monthormore)• ExtrapulmonaryCryptococcus,includingmeningitis• Anydisseminatedendemicmycosis(e.g.extrapulmonaryhistoplasmosis,coccidiomycosis,penicilliosis)• Cryptosporidiosis• Isosporiasis

Annex1.RevisedWHOclinicalstagingofHIV/AIDSforinfantsandchildren

continued on next page

425


• Disseminatednon-tuberculousmycobacteriainfection• Candidaoftrachea,bronchiorlungs• Visceralherpessimplexinfection• AcquiredHIV-associatedrectalfistula• CerebralorB-cellnon-Hodgkinlymphoma• Progressivemultifocalleukoencephalopathy(PML)• HIV-associatedcardiomyopathyorHIV-associatednephropathya

• LeiomyosarcomaandotherHIV-relatedsolidtumours

aWHOisseekingfurtherinformationandevidencerelatingtotheoccurrenceanddefinitionsoftheseconditions.Source:WHORegionalOfficeforEurope(90).

426


Annex2.WHOclassificationofHIV-associatedimmunodeficiencyininfantsandchildren

Table 20. classification of HiV-associated immunodeficiency

Classification of HIV-associated immunodeficiency

Age-related CD4 values

≤11 months (%) 12–35 months (%) 36–59 months (%) ≥5 yearsa (cells/mm3)

Notsignificant >35 >30 >25 >500Mild 30–35 25–30 20–25 350−499

Advanced 25–29 20−24 15−19 200−349Severe <25 <20 <15 <200or<15%

aIncludingadolescentsandadults.Source:WHO(30).

428


Abacavir Didanosine (twice daily) Efavirenz Lamivudine Nelfinavir

Surfacearea (m²)

Weightrange (kg) Formulation DOSE (ml

or tablets) Formulation Dose (ml or tablets) Formulation

Dose(capsules,tablets)

Formulation Dose (ml, tablets) Formulation Dose

(tablets)

Bot-tom

Top Bot-tom

Top AM PM AM PM Age 3 years and above. Dose given ONCE daily

AM PM AM PM

0.30 0.34 5.0 5.9 20 mg/ml syrup

2 ml 2 ml 10 mg/ml suspension 4 ml 4 ml 10 mg/ml solution 3 ml 3 ml 250 mg tablets

2 2

or25 mg chew tablets 2 2

0.34 0.38 6.0 6.9 20 mg/ml syrup


2 2


0.38 0.40 7.0 7.9 20 mg/ml syrup


3 2


0.40 0.43 8.0 8.9 20 mg/ml syrup


3 3


0.43 0.45 9.0 9.9 20 mg/ml syrup


3 3

or25 mg chew

tablets2 2

0.45 0.49 10 10.9 20 mg/ml syrup

5 ml 5 ml 10 mg/ml suspension 6 ml 6 ml 200 mg capsule 1 10 mg/ml solution 5 ml 5 ml 250 mg tablets

3 3


0.49 0.53 11 11.9 20 mg/ml syrup

5 ml 5 ml 10 mg/ml suspension 7 ml 7 ml 200 mg capsule 1 10 mg/ml solution 5 ml 5 ml 250 mg tablets

3 3

or or300 mg tablets

0.5 0.5 25 mg chew tablets 3 3

0.53 0.58 12 13.9 20 mg/ml syrup

6 ml 6 ml 10 mg/ml suspension 7 ml 7 ml 200 mg capsule 1 150 mg tablet 0.5 0.5 250 mg tablets

4 4

or or300 mg tablets

0.5 0.5 25 mg chew tablets 3 3

0.58 0.70 14 16.9 300 mg tablets

0.5 0.5 10 mg/ml suspension 8 ml 8 ml 200 mg capsule+

50 mg capsule

1+1

150 mg tablet 0.5 0.5 250 mg tablets

4 4


0.70 0.80 17 19.9 300 mg tablets

0.5 0.5 10 mg/ml suspension 9 ml 9 ml 200 mg capsule+

50 mg capsule

1+1

150 mg tablet 0.5 0.5 250 mg tablets

5 5

or or25 mg chew tablets 4 4 625 mg

tablets2 2

0.80 0.95 20 24.9 300 mg tablets

1 0.5 25 mg chew tablets 5 5 200 mg capsule+

100 mg capsule

1+1

150 mg tablet 1 0.5 250 mg tablets

5 5

or625 mg tablets

2 2

0.95 1.10 25 29.9 300 mg tablets

1 1 25 mg chew tablets 5 5 200 mg capsule+

100 mg capsule+

50 mg capsule

1+1+1

150 mg tablet 1 1 250 mg tablets

5 5

or625 mg tablets

2 2

1.10 1.20 30 34.9 300 mg tablets

1 1 25 mg chew tablets 5 5 200 mg capsule 2 150 mg tablet 1 1 250 mg tablets

5 5

or625 mg tablets

2 2

35 39.9 25 mg chew tablets 5 5 200 mg capsule 2 250 mg tablets

5 5

or625 mg tablets

2 2

40 andover

200 mg capsule 3

or600 mg tablet 1

429


Nevirapine (maintenance) Stavudine Zidovudine Lopinavir/ritonavir

Surfacearea (m²)

Weightrange (kg) Formulation

DOSE(ml or

tablets)Formulation Dose (ml or

tablets) Formulation Dose (ml or capsules) Formulation

Dose (ml, capsules or

tablets)Bot-tom

Top Bot-tom

Top AM PM AM PM AM PM AM PM

0.30 0.34 5.0 5.9 10 mg/ml syrup 6 ml 6 ml 1 mg/ml syrup 6 ml 6 ml 10 mg/ml syrup 6 ml 6 ml 80 mg lop/20mg rit per ml solution 1 ml 1 ml

0.34 0.38 6.0 6.9 10 mg/ml syrup 7 ml 7 ml 20 mg capsule 0.5 0.5 10 mg/ml syrup 7 ml 7 ml 80 mg lop/20mg rit per ml solution 1.5ml

1.5ml

0.38 0.40 7.0 7.9 10 mg/ml syrup 8 ml 8 ml 20 mg capsule 0.5 0.5 10 mg/ml syrup 8 ml 8 ml 80 mg lop/20mg rit per ml solution 1.5ml

1.5ml

or133 mg lop/33 mg rit per capsule 1 1

0.40 0.43 8.0 8.9 10 mg/ml syrup 9 ml 9 ml 20 mg capsule 0.5 0.5 10 mg/ml syrup 9 ml 9 ml 80 mg lop/20mg rit per ml solution 2 ml 2 mlor or

100 mg capsules 1 1 133 mg lop/33 mg rit per capsule 1 10.43 0.45 9.0 9.9 10 mg/ml syrup 9 ml 9 ml 20 mg capsule 0.5 0.5 10 mg/ml syrup 9 ml 9 ml 80 mg lop/20mg rit per ml solution 2 ml 2 ml

or or or200 mg tablets 100 mg capsules 1 1 133 mg lop/33 mg rit per capsule 1 1

0.45 0.49 10 10.9 10 mg/ml syrup 10ml

10ml

15 mg capsule 1 1 10 mg/ml syrup 10ml

10 ml 80 mg lop/20mg rit per ml solution 2 ml 2 ml

or or or200 mg tablets 0.5 0.5 100 mg capsules 1 1 133 mg lop/33 mg rit per capsule 1 1

0.49 0.53 11 11.9 10 mg/ml syrup 10ml

10ml

15 mg capsule 1 1 10 mg/ml syrup 10ml

10 ml 80 mg lop/20mg rit per ml solution 2 ml 2 ml

or or or200 mg tablets 0.5 0.5 100 mg capsules 1 1 133 mg lop/33 mg rit per capsule 1 1

0.53 0.58 12 13.9 10 mg/ml syrup 11ml

11ml

15 mg capsule 1 1 100 mg capsules 1 1 80 mg lop/20mg rit per ml solution 2 ml 2 ml

or or200 mg tablets 0.5 0.5 133 mg lop/33 mg rit per capsule 2 1

or200 mg lop/50 mg rit per tablet 1 1

0.58 0.70 14 16.9 200 mg tablets 1 0.5 20 mg capsule 1 1 100 mg capsules 2 1 80 mg lop/20mg rit per ml solution 2 ml 2 mlor or

300 mg tablets 0.5 0.5 133 mg lop/33 mg rit per capsule 2 1or

200 mg lop/50 mg rit per tablet 1 10.70 0.80 17 19.9 200 mg tablets 1 0.5 20 mg capsule 1 1 100 mg capsules 2 1 80 mg lop/20mg rit per ml solution 2.5

ml2.5ml

or or300 mg tablets 0.5 0.5 133 mg lop/33 mg rit per capsule 2 1


0.80 0.95 20 24.9 200 mg tablets 1 0.5 20 mg capsule 1 1 100 mg capsules 2 2 80 mg lop/20mg rit per ml solution 3 ml 3 mlor or

300 mg tablets 0.5 0.5 133 mg lop/33 mg rit per capsule 2 2or

200 mg lop/50 mg rit per tablet 1 10.95 1.10 25 29.9 200 mg tablets 1 1 30 mg capsule 1 1 100 mg capsules 2 2 80 mg lop/20mg rit per ml solution 3.5

ml3.5ml

or or300 mg tablets 1 0.5 133 mg lop/33 mg rit per capsule 2 2


1.10 1.20 30 34.9 200 mg tablets 1 1 30 mg capsule 1 1 100 mg capsules 3 3 80 mg lop/20mg rit per ml solution 4 ml 4 mlor or

300 mg tablets 1 1 133 mg lop/33 mg rit per capsule 3 3or

200 mg lop/50 mg rit per tablet 2 235 39.9 80 mg lop/20mg rit per ml solution 5 ml 5 ml



40 andover

80 mg lop/20mg rit per ml solution 5 ml 5 ml



Source:WHO(27).

430


Annex4.Developmentalassessmentchecklist

Table 22. developmental assessment checklist

Age Developmental milestones Date Accomplished

1month RaisesheadCrawlingmovementAlertstosound

2months HoldsheadatmidlineLiftschestofftableSmilessocially

4months RollsfronttobackLaughs

6months SitsunsupportedBabbles

9months PullstostandSays“mama”

12months WalksaloneUsesacoupleofwordstogether

18months CanremovesomeclothingScribblesUses6ormorewordstogetherRuns

24months CanwashhandsJumpsupCombineswords

36months Beginstodress(putsonshirt)UnderstandablespeechAbletobalanceononefoot

48months DressesaloneDrawsapersonUsescomplexspeechHops

Source:AdaptedfromAbrams,El-Sadr,Rabkin(56).

431


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