$mjojdbm 1spupdpm gps uif 8)0 &vspqfbo 3fhjpo · tuberculosis ... ists to monitor hiv...
TRANSCRIPT
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
393
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).
394
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).
395
Paediatric HiV/aidS treatment and care
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
396
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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.
397
Paediatric HiV/aidS treatment and care
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).
398
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
• 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.
399
Paediatric HiV/aidS treatment and care
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
2 Treatall CD4-guidedtreatmentb
3 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.
400
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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.
401
Paediatric HiV/aidS treatment and care
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).
402
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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.
403
Paediatric HiV/aidS treatment and care
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.
404
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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-
405
Paediatric HiV/aidS treatment and care
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.
406
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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).
407
Paediatric HiV/aidS treatment and care
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.
408
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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.
409
Paediatric HiV/aidS treatment and care
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.
410
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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).
411
Paediatric HiV/aidS treatment and care
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.
412
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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).
413
Paediatric HiV/aidS treatment and care
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
414
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
415
Paediatric HiV/aidS treatment and care
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.
416
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
Paediatric HiV/aidS treatment and care
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).
418
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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.
419
Paediatric HiV/aidS treatment and care
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.
420
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
Paediatric HiV/aidS treatment and care
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).
422
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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).
424
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
Paediatric HiV/aidS treatment and care
• Disseminatednon-tuberculousmycobacteriainfection• Candidaoftrachea,bronchiorlungs• Visceralherpessimplexinfection• AcquiredHIV-associatedrectalfistula• CerebralorB-cellnon-Hodgkinlymphoma• Progressivemultifocalleukoencephalopathy(PML)• HIV-associatedcardiomyopathyorHIV-associatednephropathya
• LeiomyosarcomaandotherHIV-relatedsolidtumours
aWHOisseekingfurtherinformationandevidencerelatingtotheoccurrenceanddefinitionsoftheseconditions.Source:WHORegionalOfficeforEurope(90).
426
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
3 ml 3 ml 10 mg/ml suspension 5 ml 5 ml 10 mg/ml solution 3 ml 3 ml 250 mg tablets
2 2
or25 mg chew tablets 2 2
0.38 0.40 7.0 7.9 20 mg/ml syrup
4 ml 4 ml 10 mg/ml suspension 6 ml 6 ml 10 mg/ml solution 4 ml 4 ml 250 mg tablets
3 2
or25 mg chew tablets 2 2
0.40 0.43 8.0 8.9 20 mg/ml syrup
4 ml 4 ml 10 mg/ml suspension 6 ml 6 ml 10 mg/ml solution 4 ml 4 ml 250 mg tablets
3 3
or25 mg chew tablets 2 2
0.43 0.45 9.0 9.9 20 mg/ml syrup
4 ml 4 ml 10 mg/ml suspension 6 ml 6 ml 10 mg/ml solution 4 ml 4 ml 250 mg tablets
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
or25 mg chew tablets 3 2
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
or25 mg chew tablets 4 3
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
Paediatric HiV/aidS treatment and care
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
or200 mg lop/50 mg rit per tablet 1 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
or200 mg lop/50 mg rit per tablet 2 1
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
or133 mg lop/33 mg rit per capsule 3 3
or200 mg lop/50 mg rit per tablet 2 2
40 andover
80 mg lop/20mg rit per ml solution 5 ml 5 ml
or133 mg lop/33 mg rit per capsule 3 3
or200 mg lop/50 mg rit per tablet 2 2
Source:WHO(27).
430
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
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
Paediatric HiV/aidS treatment and care
References1. EuropeanCentrefortheEpidemiologicalMonitoringofAIDS(EuroHIV).HIV/AIDS surveillance in
Europe: end-year report 2004.Saint-Maurice,InstitutdeVeilleSanitaire,2005(No.71;http://www.eurohiv.org/reports/index_reports_eng.htm,accessed24July2006).
2. FischerAetal.SimpleDNAextractionmethodfordriedbloodspotsandcomparisonoftwoPCRas-saysfordiagnosisofverticalhumanimmunodeficiencyvirustype1transmissioninRwanda.Journal of Clinical Microbiology,2004,42(1):16–20.
3. NesheimSetal.QuantitativeRNAtestingfordiagnosisofHIV-infectedinfants.Journal of Acquired Immune Deficiency Syndromes,2003,32(2):192–195.
4. RouetFetal.Pediatricviralhumanimmunodeficiencyvirustype1RNAlevels,timingofinfection,anddiseaseprogressioninAfricanHIV-1-infectedchildren.Pediatrics,2003,112(4):e289.
5. PineauFetal.ReliablediagnosisofneonatalHIV-1infectionbyrealtimePCRinCongo.11th Confer-ence on Retroviruses and Opportunistic Infections, San Francisco, 2004(AbstractNo.900).
6. RouetFetal.Transferandevaluationofanautomated,low-costreal-timereversetranscription-PCRtestfordiagnosisandmonitoringofhumanimmunodeficiencyvirustype1infectioninaWestAfricanresource-limitedsetting.Journal of Clinical Microbiology,2005,43(6):2709–2717.
7. RouziouxCetal.IsearlydiagnosisofHIVinfectionfeasibleinresource-limitedsettings?12th Confer-ence on Retroviruses and Opportunistic Infections, Boston, 2005(AbstractNo.107).
8. SchupbachJetal.HIV-1p24antigenisasignificantinversecorrelateofCD4T-cellchangeinpatientswithsuppressedviremiaunderlong-termantiretroviraltherapy.Journal of Acquired Immune Deficien-cy Syndromes,2003,33(3):292–299.
9. ShermanGG,StevensG,StevensWS.Affordablediagnosisofhumanimmunodeficiencyvirusinfec-tionininfantsbyp24antigendetection.The Pediatric Infectious Disease Journal,2004,23(2):173–176.
10. ZijenahLSetal.Signal-boostedqualitativeultrasensitivep24antigenassayfordiagnosisofsubtypeCHIV-1infectionininfantsundertheageof2years.Journal of Acquired Immune Deficiency Syndromes,2005,39(4):391–394.
11. ShermanGGetal.Polymerasechainreactionfordiagnosisofhumanimmunodeficiencyvirusinfectionininfancyinlowresourcesettings.Pediatric Infectious Disease Journal.2005;24(11):993-7.
12. DunnDTetal.ThesensitivityofHIV-1DNApolymerasechainreactionintheneonatalperiodandtherelativecontributionsofintra-uterineandintra-partumtransmission.AIDS,1995,9(9):F7–11.
13. BrysonYJetal.ProposeddefinitionsforinuteroversusintrapartumtransmissionofHIV-1.The New England Journal of Medicine,1992,327(17):1246–1247.
14. BenjaminDKJr.Integrationofstatisticaltheoryandpracticalclinicalexpertise.Polymerasechainreac-tiontestingoftheHIV-exposedinfant.Minerva Pediatrica,2002,54(2):105–111.
15. MoodleyDetal.Predictingperinatalhumanimmunodeficiencyvirusinfectionbyantibodypatterns.The Pediatric Infectious Disease Journal,1995,14(10):850–852.
16. Management of a child with a serious infection or malnutrition: guidelines for the care at the first-refer-ral level in developing countries.Geneva,WorldHealthOrganization,2000.
17. Management of serious malnutrition: a manual for physicians and other senior health workers.Ge-neva,WorldHealthOrganization,1998.
18. Nutrient requirements for people living with HIV: report of a technical consultation.Geneva,WorldHealthOrganization,2003.
19. MillerTL.NutritionalaspectsofHIV-infectedchildrenreceivinghighlyactiveantiretroviraltherapy.AIDS,2003,17(Suppl.1):S130–S140.
20. Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia,2nded.Geneva,WorldHealthOrganization,1997.
21. CoutsoudisAetal.TheeffectsofvitaminAsupplementationonthemorbidityofchildrenborntoHIV-infectedwomen.American Journal of Public Health,1995,85(8):1076–1081.
22. SfawziWWetal.ArandomizedtrialofvitaminAsupplementsinrelationtomortalityamonghumanimmunodeficiencyvirus-infectedanduninfectedchildreninTanzania.The Pediatric Infectious Disease Journal,1999,18(2):127–133.
432
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
23. VanDykeRBetal.ReportedadherenceasadeterminantofresponsetoHAARTinchildrenwhohaveHIV-infection.Pediatrics,2002,109:e61.
24. DeMartinoMetal.ReductioninmortalitywithavailabilityofantiretroviraltherapyforchildrenwithperinatalHIV-1infection.ItalianRegisterforHIVInfectioninChildrenandtheItalianNationalAIDSRegistry.JAMA,2000,284:190–197.
25. Phase IIB trial to evaluate the efficacy of oral nevirpaine and the efficacy of oralAZT in infantsborn toHIV-infectedmothers inUganda forpreventionofverticalHIV transmission (Version2.0).(HIVNET012)HIVNET/HPTNGroup, 14May2003,Seattle,Washington,USA (http://www.hptn.org/Web%20Documents/HIVNET_Protocols/HIVNET_012.pdf
26. Short-term riskofdiseaseprogression inHIV-1-infectedchildren receiving to antiretroviral therapyorzidovudinemonotherapy:ameta-analysis.HIVPaediatricPrognosticMarkersCollaborativeStudyLancet2003;362:1605-11.
27. UseoftotallymphocytecountforinformingwhentostartantiretroviraltherapyinHIV-infectedchil-dren: ameta-analysis of longitudinal data.HIVPaediatricPrognosticMarkersCollaborativeStudy.Lancet2005;366:1868-74.
28. HIVPaediatricPrognosticMarkersCollaborativeStudy[website].London,MedicalResearchCouncilClinicalTrialsUnit,2006(http://www.hppmcs.org,accessed8June2006).
29. SharlandMetal.PENTAguidelinesfortheuseofantiretroviraltherapy.HIVMedicine,BritishHIVAs-sociation,5(S2):61–86,2004(http://www.ctu.mrc.ac.uk/penta/guidelin.pdf,accessed30May2006).
30. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings, towards uni-versal access: recommendation of a public health approach: 2006.Geneva,WorldHealthOrganization,2006(http://www.who.int/hiv/pub/guidelines/WHOpaediatric.pdf,accessed19February2007).
31. HIVPaediatricPrognosticMarkersCollaborativeStudy;riskcalculator[website].London,MedicalResearchCouncilClinicalTrialsUnit,2006(http://www.ctu.mrc.ac.uk/penta/hppmcs/calcProb.htm,ac-cessed28December2006).
32. Penta5,PENTATrials[website].London,PaediatricEuropeanNetworkfor the treatmentofAIDS(PENTA),2006(http://www.ctu.mrc.ac.uk/penta/trials.htm,accessed23February2007).
33. GibbDM,etal.EvolutionofantiretroviralphenotypicandgenotypicdrugresistanceinantiretroviralnaïveHIV-1infectedchildrentreatedwithabacavir/lamivudine,zidovudine/lamivudineorabacavir/zi-dovudine,withorwithoutnelfinavir(thePENTA5trial).Antiviral Therapy 2002; 7(4):293-303 (http://www.ctu.mrc.ac.uk/penta/p5avt02.pdfaccessedon23February2007).
34. RamosJTetal. PrevalenceoflipodystrophyandhyperlipidemiainalargecohortofHIV-infectedchil-dren,12th Conference on Retroviruses and Opportunistic Infections Boston2005;(AbstractNo.775)(http://www.aegis.org/conferences/croi/2005/775.html,accessedon28December2006)
35. BHIVAWritingCommittee,GazzardBetal.DraftBHIVAguidelinesforthetreatmentofHIV-infectedadultswithantiretroviral therapy(2006)forconsultation.(http://www.bhiva.org/guidelines/2006/hiv/hivfs06.html,accessedon28December2006).
36. HandforthJ,SharlandM.Triplenucleosidereversetranscriptaseinhibitortherapyinchildren.Paediat-ric Drugs,2004,6(3):147–159.
37. GulickRMetal.Triple-nucleosideregimensversusefavirenz-containingregimensfortheinitialtreat-mentofHIV-1infection.The New England Journal of Medicine,2004,350(18):1850–1861.
38. StaszewskiSetal.Abacavir-lamivudine-zidovudinevs.indinavir-lamivudine-zidovudineinantiretro-viral-naiveHIV-infectedadults:arandomizedequivalencetrial.JAMA,2001,285(9):1155–1163.
39. EshlemanSHetal.Selectionandfadingofresistancemutationsinwomenandinfantsreceivingnevi-rapinetopreventHIV-1verticaltransmission(HIVNET012).AIDS,2001,15(15):1951–1957.
40. MandelbrotLetal.Lamivudine-zidovudinecombinationforpreventionofmaternal-infanttransmissionofHIV-1.JAMA,2001,285(16):2083–2093.
41. BulterysMet al.Combinationantiretroviral therapy inAfricannursingmothers anddrugexposurein their infants: new pharmacokinetic and virologic findings. Journal of Infectious Diseases, 2005,192(5):709–712.
42. ShapiroRLetal.Antiretroviralconcentrationsinbreast-feedinginfantsofwomeninBotswanareceiv-ingantiretroviraltreatment.Journal of Infectious Diseases, 2005,192(5):720–727.
433
Paediatric HiV/aidS treatment and care
43. WatsonDC,FarleyJJ.Efficacyof,andadherenceto,highlyactiveantiretroviraltherapyinchildreninfectedwithhumanimmunodeficiencyvirustype1.The Pediatric Infectious Disease Journal,1999,18(8):682–689.
44. FarleyJetal.AssessmentofadherencetoantiviraltherapyinHIV-infectedchildrenusingtheMedica-tionEventMonitoringSystem,pharmacyrefill,providerassessment,caregiverself-reportandappoint-mentkeeping.Journal of Acquired Immune Deficiency Syndromes,2003,33(2):211–218.
45. GibbDMetal.Adherencetoprescribedantiretroviraltherapyinhumanimmunodeficiencyvirus-in-fectedchildreninthePENTA5trial.The Pediatric Infectious Disease Journal,2003,22(1):56–62.
46. SaitohAetal.AnMDR1-3435variantisassociatedwithhigherplasmanelfinavirlevelsandmorerapidvirologicresponseinHIV-1infectedchildren.AIDS,2005,19(4):371–380.
47. MachadoDMet al.AnalysisofHIV-type1proteaseand reverse transcriptase inBrazilianchildrenfailinghighlyactiveantiretroviraltherapy(HAART).Revista do Instituto de Medicina Tropical de São Paulo,2005,47(1):1–5.
48. LindseyJCetal.Treatment-mediatedchangesinhumanimmunodeficiencyvirus(HIV)type1RNAandCD4cellcountsaspredictorsofweightgrowthfailure,cognitivedecline,andsurvivalinHIV-in-fectedchildren.Journal of Infectious Diseases, 2000,182(5):1385–1393.
49. HirschHHetal.ImmunereconstitutioninHIV-infectedpatients.Clinical Infectious Diseases,2004,38(8):1159–1166.
50. JevtovicDJetal.TheprevalenceandriskofimmunerestorationdiseaseinHIV-infectedpatientstreatedwithhighlyactiveantiretroviraltherapy.HIV Medicine, 2005,6(2):140–143.
51. ShelburneSAetal.Incidenceandriskfactorsforimmunereconstitutioninflammatorysyndromeduringhighlyactiveantiretroviraltherapy.AIDS,2005,19(4):399–406.
52. PuthanakitT.Immunereconstitutionsyndromeafterhighlyactiveantiretroviraltherapyinhumanim-munodeficiencyvirus-infectedThaichildren. Pediatric Infectious Diseases Journal,2006,25(1):53–58.
53. TangsinmankongNetal.Varicella zosterasamanifestationofimmunerestorationdiseaseinHIV-in-fectedchildren.Journal of Allergy and Clinical Immunology,2004,113(4):742–746.
54. NuttallJJetal.Progressivemultifocalleukoencephalopathyafterinitiationofhighlyactiveantiretrovi-raltherapyinachildwithadvancedhumanimmunodeficiencyvirusinfection:acaseofimmunerecon-stitutioninflammatorysyndrome.The Pediatric Infectious Disease Journal,2004,23(7):683–685.
55. ShelburneSA,MontesM,HamillRJ.Immunereconstitutioninflammatorysyndrome:moreanswers,morequestions.The Journal of Antimicrobial Chemotherapy,2005,57(2):167–170.
56. AbramsE,El-SadrW,RabkinM.ThePediatricClinicalManual.The International Center for AIDS Programs. NewYork, ColumbiaUniversityMailmanSchoolofPublicHealth,2004(http://www.co-lumbia-icap.org/clinicalunit/pdf/cm/Pediatric_Clinical_Manual.pdf,accessed28December2006).
57. ChaseCetal.EarlyCognitiveandmotordevelopmentamonginfantsborntowomeninfectedwithhu-manimmunodeficiencyvirus.Pediatrics2000,106(2):e25.
58. TheEuropeanCollaborativeStudy.Height,weight,andgrowthinchildrenborntomotherswithHIV-1infectioninEurope.Pediatrics2003,111(1):e52-e60.
59. ChakrabortyR,ShingadiaD.Treating Opportunistic Infections In HIV-Infected Children Guidelines for the Children’s HIV Association(CHIVA)[website].London,Children’sHIVAssociation(CHIVA),September2006,accessed23February2007).
60. DunnA-M,TizerK,CerviaJS.Rifabutin-associateduveitisinapediatricpatient.The Pediatric Infec-tious Disease Journal,1995,14:246–247.
61. ChintuCetal.CotrimoxazoleasprophylaxisagainstopportunisticinfectionsasHIV-infectedZambianchildren (CHAP): adouble-blind randomisedplacebo-controlled trial.The Lancet, 2004,364:1865–18671.
62. GrahamSMetal.ClinicalpresentationandoutcomeofPneumocystis cariniipneumoniainMalawianchildren.The Lancet,2000,355:369–373.
63. RiordanA.The child with HIV and respiratory illness.London,BritishHIVAssociation,2005(http://www.bhiva.org/chiva/protocols/respiratory.html,accessed22May2006).
434
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
64. Report of a WHO expert consultation on cotrimoxazole prophylaxis in HIV infection.Geneva,WorldHealth Organization, 2005 (WHO Technical Report Series; http://www.who.int/hiv/pub/meetingre-ports/ctxprophylaxismeeting.pdf,accessed24May2006).
65. Guidelines for cotrimoxazole prophylaxis for HIV-related infections in children, adolescents and adults in resource limited settings: recommendations for a public health approach.Geneva,WorldHealthOrganization.
66. RenoldCetal.Toxoplasmaencephalitis inpatientswith theacquired immunodeficiencysyndrome.Medicine,1992;71(4):224-39.
67. MitchellCDetal.Congenitaltoxoplasmosisoccurringininfantsperinatallyinfectedwithhumanim-munodeficiencyvirus1.Pediatric Infectious Disease Journal,1990;9:512–8.
68. MontoyaJG,RemingtonJS.Toxoplasmagondii.In:MandellGL,BennettJE,DolinR,eds.PrinciplesandPracticeofInfectiousDiseases.Philadelphia:ChurchillLivingstone,2000;2858-2888.
69. PostMJetal.CranialCTinacquiredimmunodeficiencysyndrome:spectrumofdiseasesandoptimalcontrastenhancementtechnique.American Journal of Roentgenol1985;145(5):929-40.
70. LevyRMetal.TheefficacyandclinicalimpactofbrainimaginginneurologicallysymptomaticAIDSpatients:aprospectiveCT/MRIstudy.Journal of Acquired Immune Deficiency Syndrome,19903(5):461-71.
71. CiricilloSF,RosenblumML.ImagingofsolitarylesionsinAIDS.JNeurosurg1991;74(6):1029.72. Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal candidiasis and carriage
ofCandidaalbicansassociatedwith trends toward reduced ratesofcarriageof fluconazole-resistantC. albicans in human immunodeficiencyvirus-infectedpatients.Clinical Infectious Diseases, 1998;27(5):1291-4
73. GottfredssonMetal.Associationofplasmalevelsofhumanimmunodeficiencyvirustype1RNAandoropharyngealCandidacolonization.Journal of Infectious Diseases,1999;180(2):534-7.
74. Fichtenbaum CJ et al. Refractory mucosal candidiasis in advanced human immunodeficiency virusinfection.Clinical Infectious Diseases,2000;30(5):749-56
75. MullerFM,GrollAH,WalshTJ.Currentapproachestodiagnosisandtreatmentoffungalinfectionsin children infected with human immuno deficiency virus. European Journal of Pediatrics, 1999,158:187–199.
76. WalshTJetal.Fungemiainchildreninfectedwiththehumanimmunodeficiencyvirus:newepidemio-logicpatterns,emergingpathogensandimprovedoutcomewithantifungaltherapy.Clinical Infectious Diseases,1995,20:900–906.
77. NigroGetal.RapidprogressionofHIVdiseaseinchildrenwithcytomegalovirusanaemia.AIDS,1996,10:1127–1133.
78. MartinDFetal.Acontrolledtrialofvalganciclovirasinductiontherapyforcytomegalovirusretinitis.The New England Journal of Medicine,2002,346:1119–1126.
79. LeibovitzEetal.Chronicvaricella-zosterinachildinfectedwithhumanimmunodeficiencyvirus:casereportandreviewoftheliterature.Cutis,1992;49:27–31.
80. vonSeidleinLetal..Frequentrecurrenceandpersistenceofvaricella-zostervirusinfectionsinchildreninfectedwithhumanimmunodeficiencyvirustype1.Journal of Pediatrics,1996;128(1):52-7.
81. SillimanCCetal.Unsuspectedvaricella-zostervirusencephalitisinachildwithacquiredimmunodefi-ciencysyndrome.Journal of Pediatrics,1993;123:418–22.
82. CDC.GuidelinesforthepreventionofopportunisticinfectionsamongHIV-infectedpersons—recom-mendationsoftheU.S.PublicHealthServiceandtheInfectiousDiseaseSocietyofAmerica.Morbidity and mortality weekly report,2002;51(No.RR-8).MMWR.Availableat:http://AIDSInfo.nih.gov.
83. WhitleyR,KimberlinD,RoizmanB.Herpes simplexviruses.Clinical Infectious of Diseases,1998,26:541–553.
84. KimberlinDWetal.NaturalhistoryofneonatalHerpes simplexvirusinfectionsintheacyclovirera.Pediatrics,2001,108:223–229.
85. KimberlinDWetal.ApplicationofthepolymerasechainreactiontothediagnosisandmanagementofneonatalHerpes simplexvirusdisease.Journal of Infectious Diseases,1996,174:1162–1167.
435
Paediatric HiV/aidS treatment and care
86. HilgartnerMWetal.Theeffectofplasmahuman immunodeficiencyvirusRNAandCD4+T lym-phocytesongrowthandmeasurementsofhemophilicboysandadolescents.Pediatrics,2001,107(4):E56.
87. GaughanDMetal.Avascularnecrosisofthehip(Leggs-Calve-PerthesDisease)inHIV-infectedchil-dren in long-term follow-up:PACTGstudy219.8th Conference on Retroviruses and Opportunistic Infections, Chicago, 4–8 February 2001(Abstract638;http://www.retroconference.org/2001/abstracts/abstracts/abstracts/638.htm,accessed13June2006).
88. SchwartzL,HouckCS.PainmanagementforchildrenwithHIV.In:Nedeljkovic,SS,ed.Pain manage-ment, anesthesia, and HIV/AIDS.NewYork,ElsevierScienceHealth,2002.
89. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Boston,ButterworthHein-emann,2005(http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf,accessed18June2006).
90. Report of the technical consultation on clinical staging of HIV/AIDS and HIV/AIDS case definition for surveillance.Copenhagen,WHORegionalOfficeforEurope,2005(http://www.euro.who.int/docu-ment/E87956.pdf,accessed19December2006).