HIV/AIDS Programme · HIV human immunodeficiency virus PMTCT prevention of mother to child transmission ( of HIV) RNA ribonucleic acid WHO World Health Organization EIA Enzyme Immunoassay

WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE

AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL

CLASSIFICATION OF HIV-RELATED DISEASE

IN ADULTS AND CHILDREN

Strengthening health services to fight HIV/AIDS

HIV/AIDS Programme

WHO Library Cataloguing-in-Publication Data

WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children.

1.HIV infections - diagnosis. 2.HIV infections - classification. 3.Disease progression. 4.Epidemiologic surveillance - standards. 5.Disease notification - standards. I.World Health Organization.

ISBN 978 92 4 159562 9 (NLM classification: WC 503.1)

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WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE

AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL

CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN

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Abbreviations 4

Introduction................................................................................................................................. 5

Background................................................................................................................................. 6

SurveillanceandcasereportingforHIV...................................................................................... 7

WHOcasedefinitionforHIVinfection.......................................................................................... 8

WHOcasedefinitionforadvancedHIV(infectionordisease)(includingAIDS)......................... 9

PrimaryHIVinfection................................................................................................................. 10

ClinicalandimmunologicalclassificationforHIVandrelateddisease......................................11

Table1. WHOclinicalclassificationofestablishedHIVinfection.......................................... 12Table2. WHOimmunologicalclassificationforestablishedHIVinfection............................. 15

Annex1. PresumptiveanddefinitivecriteriaforrecognizingHIV-relatedclinicaleventsamongadults(15yearsorolder)andamongchildren(youngerthan15years)withconfirmedHIVinfection.............................................. 19

Annex2. PresumptivediagnosisofsevereHIVdiseaseamongHIV-seropositiveHIV-exposedchildren............................................................................................... 39

References................................................................................................................................. 40

CONTENTS

� WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN

AbbREVIATIONS

AIDS acquiredimmunodeficiencysyndromeART antiretroviraltherapyCD�+ T-lymphocytebearingCD4receptorCDC UnitedStatesCentersforDiseaseControlandPreventionDNA deoxyribonucleicacidHIV humanimmunodeficiencyvirusPMTCT preventionofmothertochildtransmission(ofHIV)RNA ribonucleicacidWHO WorldHealthOrganizationEIA EnzymeImmunoassayELISA Enzyme-LinkedimmunosorbentassayS/R Test SimpleorRapidHIVantibodytest

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INTRODUCTION

Witha view to facilitating thescalingupofaccess toantiretroviral therapy,and in linewithapublic health approachi, this publication outlines recent revisions WHO has made to casedefinitionsforsurveillanceofHIVandtheclinicalandtheimmunologicalclassificationforHIV-relateddisease.HIVcasedefinitionsaredefinedandharmonizedwiththeclinicalstagingandimmunologicalclassificationstofacilitateimprovedHIV-relatedsurveillance,tobettertracktheincidence, prevalence and treatment burden of HIV infection and to plan appropriate publichealth responses. The revised clinical staging and immunological classification of HIV aredesigned toassist inclinicalmanagementofHIV,especiallywhere there is limited laboratorycapacity.ThefinalrevisionsoutlinedherearederivedfromaseriesofregionalconsultationswithMember States in all WHO regions held throughout 2004 and 2005, comments from publicconsultationandthedeliberationsofaglobalconsensusmeetingheldinApril2006.

Inmostcountries, reportingofacquired immunodeficiencysyndrome (AIDS)caseshasbeenincompleteandchildrenarerarelyincluded.Further,timelyandappropriateuseofantiretroviraltherapydelaysandmaypreventthedevelopmentofAIDSaspreviouslydefined.Theadvancesinantiretroviraltherapy(ART)thereforemeanthatpublichealthsurveillanceofAIDSalonedoesnot provide reliable population-based information on the scale and magnitude of the HIVepidemic. Data on adults and children diagnosed with HIV infection are more useful fordeterminingpopulationsneedingpreventionandtreatmentservices.

SimplifiedHIVcasedefinitionsareprovidedbasedonlaboratorycriteriacombinedwithclinicalorimmunologicalcriteria.TheclinicalstagingofHIV-relateddiseaseforadultsandchildrenandthesimplifiedimmunologicalclassificationareharmonizedtoauniversalfour-stagesystemthatincludes simplified standardized descriptors of clinical staging events. The revised HIV casedefinitionsandtheclinicalandimmunologicalclassificationsystemproposedareintendedforconductingpublichealthsurveillanceandforuseinclinicalcareservices.WHOrecommendsthatnationalprogrammesreviewandstandardizetheirHIVandAIDScasereportingandcasedefinitionsinthelightoftheserevisions.

i Thepublichealthapproachtoantiretroviraltherapyisdefinedinthefollowingarticle:TheWHOpublic-healthapproachtoan-tiretroviraltreatmentagainstHIVinresource-limitedsettings.C Gilks, S Crowley, R Ekpini, et al. Lancet(Vol.368,August2006,505–510).


In 1986, WHO developed a provisional clinical AIDS case definition for adults and children(Banguidefinition)[1]toreportAIDScasesinresource-constrainedsettings[2, 3].Thedefinitionwas formalized in 1986 and modified in 1989 (for adults and adolescents only) to includeserological HIV testing and then modified again in 1994 to accommodate 1993 revisions toEuropean and United States Centers for Disease Control and Prevention definitions [3-12].European and United States Centers for Disease Control and Prevention definitions includespecificcasedefinitionsforchildren.StudiesinAfricansettings[13-15]suggestthattheoriginalWHOclinicalcasedefinitionsforAIDSinchildrenarenotverysensitiveorspecific.AIDScasereportinginmiddle-andlow-incomecountrieshasbeenincompleteandofvariableaccuracy,which has hampered its utility. Underreporting and delays in notification are frequent andexacerbatedbyweakheath informationsystemsand the lackofdiagnosticcapacity. Inhigh-income countries, AIDS case reporting combined with active AIDS case-finding has allowedAIDS notification and AIDS specific mortality to be monitored. However, the widespreadavailability of successful antiretroviral therapy means that both new AIDS cases and AIDSmortalityhavebeendecliningincountrieswithhighcoverageofantiretroviraltherapy.

bACkGROUND

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Thescale-upofservicesforART,preventingmother-to-childtransmissionofHIV(PMTCT)andHIVcounsellingandtestinghasledtoanincreaseinthenumbersofadultsandchildrenbeingtested and diagnosed with HIV infection. Accurate data are needed on adults and childrendiagnosedwithHIVinfectiontofacilitateestimationofthetreatmentandcareburden,toplanforeffective prevention and care interventions and assess care interventions. WHO thereforerecommends that countries consider conducting reporting of newly diagnosed cases of HIVinfectioninadultsandchildren(Box1).TherequirementsfortheconfidentialityandsecurityofHIVsurveillancedataarethesameasforAIDS-relatedreporting.Provider-initiatedreportingwillbe required to increase the completeness, timeliness and efficiency of HIV case reporting.Laboratory-initiated reportingalonewillbe insufficient for reportingHIV,asothersurveillanceinformationfromthehealthcareproviderormedicalrecordswillberequired.

ForthepurposesofHIVcasedefinitionsforreportingandsurveillance,childrenaredefinedasyoungerthan15yearsofageandadultsas15yearsorolderi.

i ForthepurposesoftheUnitedNationsConventionontheRightsoftheChild,achildisahumanbeingyoungerthan18years,unlessunderthelawapplicabletothechild,majorityisattainedearlier.TheUnitedNationsGeneralAssemblydefinesyouthaspeople15–24yearsold.AllUnitedNationsstatisticsonyoutharebasedonthisdefinition,andchildrenarethereforefrequentlyassumedtobepeople14yearsoldandyounger.Aninfantisachildfrombirthuptoageoneyear.

SURVEILLANCE AND CASE REpORTING FOR HIV


WHO case definitiOn fOr HiV infectiOn

To facilitate the reporting of HIV infection, WHO recommends the following:

HIV cases diagnosed and not previously reported in each country should be reported according to a standard national case definition. A case of HIV infection is defined as an individual with HIV infection irrespective of clinical stage (including severe or stage 4 clinical disease, also known as AIDS) confirmed by laboratory criteria according to country definitions and requirements. Countries should develop and regularly review their testing algorithms for diagnostic and

surveillance purposes.i WHO provides a simplified HIV case definition designed for reporting and surveillance (Box 1).

HIV infection is diagnosed based on laboratory criteria. Clinically diagnosing suspected or probable HIV infection by diagnosing an AIDS-defining condition or HIV at any immunological stage in an adult or child requires confirmation of HIV infection by the best age-appropriate test. Further, as maternal HIV antibody transferred passively during pregnancy can persist for as long as 18 months among children born to mothers living with HIV, positive HIV antibody test results are difficult to interpret in younger children, and alternative methods of diagnosis are recommended.

Box 1. WHO case definition for HIV infection

Adults and children 1� months or olderHIV infection is diagnosed based on:

positive HIV antibody testing (rapid or laboratory-based enzyme immunoassay). This is confirmed by a second HIV antibody test (rapid or laboratory-based enzyme immunoassay) relying on different antigens or of different operating characteristics;

and/or;

positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by a second virological test obtained from a separate determination.

Children younger than 1� months:HIV infection is diagnosed based on:

positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive HIV p24 antigen) confirmed by a second virological test obtained from a separate

determination taken more than four weeks after birth1.Positive HIV antibody testing is not recommended for definitive or confirmatory diagnosis of HIV infection in children until 18 months of age.

i Further technical information on algorithms for HIV testing by WHO can be found at http://www.who.int/diagnostics_laboratory/ evaluations/hiv/en/index.html.

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WHO case definitiOn Of adVanced HiV (infectiOn Or disease) (including aids) fOr repOrting:

Cases diagnosed with advanced HIV infection (including AIDS) not previously reported should be reported according to a standard case definition. Advanced HIV infection is diagnosed based on clinical and/or immunological (CD4) criteria among people with confirmed HIV infection (Box 2).

Box 2. Criteria for diagnosis of advanced HIV (including AIDSa) for reporting

Clinical criteria for diagnosis of advanced HIV in adults and children with confirmed HIV infection:presumptive or definitive diagnosis of any stage 3 or stage 4 conditionb.

and/or;

Immunological criteria for diagnosing advanced HIV in adults and children five years or older with confirmed HIV infection:CD4 count less than 350 per mm3 of blood in an HIV-infected adult or child.

and/or;

Immunological criteria for diagnosing advanced HIV in a child younger than five years of age with confirmed HIV infection:%CD4+ <30 among those younger than 12 months;

%CD4+ <25 among those aged 12–35 months;

%CD4+ <20 among those aged 36–59 months.

a AIDS in adults and children is defined as; clinical diagnosis (presumptive or definitive ) of any stage 4 condition (defined in Annex 1) with confirmed HIV infection: OR immunological diagnosis in adults and children with confirmed HIV infection and >5 years of age; first-ever documented CD4 count less than 200 per mm3 or %CD4+ <15: OR among children with confirmed HIV infection aged 12–35 months first ever documented %CD4 <20: OR among children with confirmed HIV infection and less than 12 months of age first ever documented %CD4 <25.

b Annex 1 provides criteria for presumptive or definitive diagnosis of all conditions.

AIDS case reporting for surveillance is no longer required if HIV infection or advanced HIV infection is reported.

10 WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN

ThereisnostandarddefinitionofprimaryHIVinfection.However,reportingprimaryHIVinfection,where recognized and documented, is useful and should be encouraged. The United StatesCentersforDiseaseControlandPrevention(CDC)areexpectedtodevelopacasedefinitionforreporting primary HIV infection. Primary HIV infection can be recognized in infants, children,adolescents and adults; it can be asymptomatic or be associated with features of an acuteretroviralsyndromeofvariableseverity [16-21].Primary infectionusuallypresentsasanacutefebrileillness2–4weekspostexposure,oftenwithlymphadenopathy,pharyngitis,maculopapularrash,orogenitalulcersandmeningoencephalitis.Profound transient lymphopaenia (includinglowCD4)candevelop,andopportunisticinfectionsmayoccur,buttheseinfectionsshouldnotbeconfusedwithclinicalstagingeventsdeveloping inestablishedHIV infection.PrimaryHIVinfectioncanbeidentifiedbyrecentappearanceofHIVantibodyorbyidentifyingviralproducts(HIV-RNAorHIV-DNAand/orultrasensitiveHIVp24antigen)withnegative(orweaklyreactive)HIVantibody[16, 22, 23].

pRIMARy HIV INFECTION

11

Initially in1990,a four-stageclinicalstagingsystemwasdeveloped forclinicalpurposesandonlyforadults[24].Subsequently in2002,athree-stagesystemforchildrenwasproposedtosupport rolling out ART [25]. This publication revises the 2003 WHO clinical staging of HIV-relateddiseaseininfantsandchildren,whichisnowharmonizedwiththe1990classificationofdiseaseforadultsandadolescents.Thisissimilartothefour-stageclinicalclassificationoftheUnitedStatesCDCrevisedin1994andoriginallyintendedforsurveillancepurposes[26].BoththeUnitedStatesCDCandWHOclinical classifications recognizeprimaryHIV infection. It isalsoproposedthattheappearanceofneworrecurrentclinicalstagingeventsorimmunodeficiencybeusedtoassessindividualsoncetheyarereceivingART.

Clinical assessment prior to treatment

Clinicalstaging isusedonceHIV infectionhasbeenconfirmed(serologicaland/orvirologicalevidenceofHIV infection).AnadditionalpresumptiveclinicaldiagnosisofsevereHIVdisease(equivalenttosevereimmunodeficiency)amonginfantsyoungerthan18monthsissuggestedforuseinsituationsinwhichdefinitivevirologicaldiagnosisofHIVinfectionisnotreadilyavailable(Annex2).

The clinical events used to categorize HIV disease among infants, children, adolescents oradultslivingwithHIVaredividedintothoseforwhichapresumptiveclinicaldiagnosismaybemade (where syndromes or conditions can be diagnosed clinically or with basic ancillaryinvestigations) and those requiring a definitive diagnosis (generally conditions describedaccordingtocausationrequiringmorecomplexorsophisticatedlaboratoryconfirmation).Table1 provides the clinical stage in simplified terms describing the spectrum of HIV relatedsymptomatology,asymptomatic,mildsymptoms,advancedsymptomsandseveresymptoms.Tables3and4summarizetheclinicalstagingevents,andAnnex1providesfurtherdetailsofthespecificeventsandthecriteriaforrecognizingthem.

Theclinicalstageisusefulforassessmentatbaseline(firstdiagnosisofHIVinfection)orentryinto long-termHIVcareand in the follow-upofpatients incareand treatmentprogrammes. Itshouldbeusedtoguidedecisionsonwhentostartco-trimoxazoleprophylaxisandotherHIV-relatedinterventions,includingwhentostartantiretroviraltherapy.Theclinicalstageshavebeenshowntoberelatedtosurvival,prognosisandprogressionofclinicaldiseasewithoutantiretroviraltherapyinadultsandchildren [27-38].i

i ThroughtheconsultationprocesswithWHOMemberStates,HIVexpertshavesuggestedthat,ifthreeormoreconditionsfromanyoneclinicalstagearepresentatthesametime,theclinicalstagemaybeconsideredtobehigher.Forexample,concurrentpresence of three or more stage 2 clinical events would suggest clinical stage 3. However, adopting this approach requiresfurtherstudy.

CLINICAL AND IMMUNOLOGICAL CLASSIFICATION OF HIV AND RELATED DISEASE


Table 1. WHO clinical staging of established HIV infection

HIV-associated symptoms WHO clinical stage

Asymptomatic 1

Mildsymptoms 2

Advancedsymptoms 3

Severesymptoms 4

Clinical assessment of people receiving antiretroviral therapy

Treatment with potent and effective antiretroviral therapy regimens can reverse and improveclinicalstatusinkeepingwithimmunerecoveryandsuppressionofviralload[37, 39-41].Neworrecurrentclinicalstagingeventsoncepeoplearereceivingantiretroviraltherapyformorethan24weeksmaybeusedtoguidedecision-making,particularlywhentheCD4countisnotavailable.It is assumed that the clinical staging events remain significant among people receivingantiretroviral therapy as they are among children and adults before the start of antiretroviraltherapy.Inthefirst24weeksofstartinganantiretroviraltherapyregimen,clinicaleventsappearlargelydue to immune reconstitution [42-46] (or the toxicityof antiretroviral therapy); after 24weeks,clinicaleventsusuallyreflectimmunedeterioration.However,themonitoringofdiseaseprogression and response to therapy using clinical staging events urgently needs to bevalidated.

Immunological assessment

ThepathogenesisofHIVinfectionislargelyattributabletothedecreaseinthenumberofTcells(aspecifictypeoflymphocyte)thatbeartheCD4receptor(CD4+).Theimmunestatusofachildor adult living with HIV can be assessed by measuring the absolute number (per mm3) orpercentageofCD4+cells,andthisisregardedasthestandardwaytoassessandcharacterizetheseverityofHIV-relatedimmunodeficiency.ProgressivedepletionofCD4+Tcellsisassociatedwith progression of HIV disease and an increased likelihood of opportunistic infections andotherclinicaleventsassociatedwithHIV,includingwastinganddeath[47-52].

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Immune status in children

TheabsoluteCD4cellcountandthe%CD4+inhealthyinfantswhoarenotinfectedwithHIVareconsiderablyhigherthanthoseobservedinuninfectedadultsandslowlydeclinetoadultvaluesbytheageofaboutsixyears.AgemustthereforebetakenintoaccountasavariableinconsideringabsoluteCD4countsor%CD4+[50, 53-59].Amongchildrenyoungerthanfiveyearsofage,theabsolute CD4 count tends to vary within an individual child more than the %CD4+. Currently,therefore,themeasurementofthe%CD4+isthoughttobemorevaluableinyoungerchildreni.Absolute CD4 counts (and less so %CD4+) fluctuate within an individual and depend onintercurrentillness,physiologicalchangesortestvariability.Measuringthetrendovertwoorthreerepeated measurements is therefore more informative than an individual value. Not all theequipment in use in resource-constrained settings can accurately estimate the %CD4+. ThededicatedcytometersaredesignedtoexclusivelyperformabsoluteCD4measurementswithouttheneedforahaematologyanalyserandthereforedonotprovide%CD4+ii.

Anyclassificationofimmunestatushastoconsiderage.The1994immunologicalclassificationof the United States CDC has previously been used [60]. WHO has proposed a modifiedimmunological classification based on more recent analysis of the prognosis. Analysis ofprognosisfrom17studiesofchildrenincluding3941childrenlivingwithHIVfromUnitedStatesandEuropeansettingsprovideestimationsofCD4andage-relatedriskofprogressiontoAIDSordeath[50].A%CD4+of35isassociatedwitha15%riskofprogressiontoAIDSinthenext12monthsamongchildrenagedthreemonthsandan11%riskamongthosesixmonthsold.TherevisedWHOclassificationattemptstobetterreflectthisincreasedriskintheseyoungerchildren.Basedonreanalysisof thedata, the thresholds forsevere immunodeficiency inchildrenhavebeen revised [30]. For children in the WHO classification, age-related severe HIV-relatedimmunodeficiency is defined as values at or below age-related CD4 thresholds below whichchildrenhaveagreaterthan5%chanceofdiseaseprogressiontosevereclinicalevents(AIDS)ordeathinthenext12months.Furtherresearchisurgentlyrequiredtoassesstheprognosticsignificance and to ascertain normal and disease-associated CD4 levels among African andAsian children [61]. Note that, among children younger than one year, the immunologicalcategoriesdonotreflectthesamelevelofriskatanygivenage;thus,achildsixmonthsoldhasahigher riskofprogression foranygivenCD4count thanachild11monthsold.However, tofacilitate the scaling up of access to antiretroviral therapy, WHO proposes this simplifiedharmonizedimmunologicalclassificationsystemforadultsandchildren.Theimmuneparametersandthereforeclassificationimprovewithsuccessfulantiretroviraltherapy(Table2)[30, 62-67].Immune parameters can be used to monitor the response to antiretroviral therapy, and it ishopedthattheimmunologicalclassificationwillfacilitatethis.

i Tocalculatethe%CD4+,usethefollowingformula:%CD4+=(absolutecountCD4(mm3)times100)/absolutetotallymphoctyecount(mm3).

ii WHOguidanceonCD4technologyisavailableat:http://www.who.int/diagnostics_laboratory/CD4_Technical_Advice_ENG.pdf.

1� WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN

Immune status in adults

ThenormalabsoluteCD4count inadolescentsandadults ranges from500 to1500cellspermm3ofblood.Ingeneral,theCD4(%CD4+orabsolutecount)progressivelydecreasesasHIVdisease advances. As in children, individual counts may vary within an individual adult oradolescentandassessingtheCD4countovertimeismoreuseful[68-73].TheCD4countusuallyincreases in response to effective combination antiretroviral therapy, although this may takemanymonths [74-78]. Theproposed immunological classificationoutlines fourbandsofHIV-related immunodeficiency (Table2):nosignificant immunodeficiency,mild immunodeficiency,advanced immunodeficiency and severe immunodeficiency. The likelihood of diseaseprogression to AIDS or death without ART increases with increasing immunodeficiency(decreasingCD4)[79], opportunisticinfectionsandotherHIVrelatedconditionsareincreasinglylikely with CD4 counts below 200 per mm3 [29, 80, 81]. Response to ART is affected by theimmunestageatwhichitisstarted,peoplecommencingARTwithadvancedimmunodeficiency(CD4>200–350permm3)appeartohavebettervirologicaloutcomesthanthosewhocommencewithmoresevereimmunodeficiency.AdultsstartingARTwithCD4<50permm3haveamuchgreaterriskofdeath[37, 40, 41, 76].AdultswhocommenceARTwithonlymildimmunodeficiencydo not appear to obtain any additional benefits [41]. Revised antiretroviral therapyrecommendationsreflectthis.iPregnancydoesaffecttheCD4countalthoughthesignificanceofthesechangesisnotclearlyunderstood[58, 82],andforpracticalpurposestheimmunologicalclassificationremainsthesame.

Clinical decision-making

RegardlessofageorclinicalstageCD4testingisveryvaluableandshouldbeencouraged.Itisusefultoguidethedecisiononinitiationofco-trimoxazoleandwhentostartfirst-lineARTortoidentifytreatmentfailureandtheneedtoswitchtoasecond-lineregimenofART.MeasurementofCD4canalsobeusedtoassessandmonitorresponsetoART.

Whereclinicalandimmunologicalclassificationsarebothavailable,immunestatus,reflectedbyCD4(%CD4+orabsolutecount)isusuallymoreinformative.Thisisreflectedinthemostup-to-dateWHOrecommendationsonARTforinfants,childrenandadults.iiInyoungerchildren%CD4+shouldbeused,andfromfiveyearsofagetheabsolutecountispreferred.

Severe HIV-related disease always requires ART irrespective of whether defined by clinicalconditionorimmunestatus.AdvancedHIVdiseasebasedonimmunestatusrequiresconsideringART,especiallywhendisease isadvancedasdefinedclinically.Startingantiretroviral therapycan usually be delayed if the immune status suggests that there is only mild or insignificantimmunodeficiency(%CD4+>30amongchildrenyoungerthan12months,>25amongchildren12–35monthsor>20 inchildrenover36months,orCD4count>350permm3 inadultsandolderchildren),andtheindividualisasymptomaticoronlyhasmildsymptoms.

i WHOrecommendationsforantiretroviraltherapyforadultsandchildrenandantiretroviraldrugsforpreventingmother-to-childtransmissionhavebeenrevisedin2006.DetailsareavailableontheWHOwebsiteat:

ii Availableathttp://www.who.int/hiv/pub/guidelines/arv/en/index.html.

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Table 2. WHO immunological classification for established HIV infection

HIV-associated immunodeficiency

Age-related CD� values

<11 months

(%CD�+)

12–�� months

(%CD�+)

��–�� months

(%CD�+)

>� years (absolute number

per mm� or %CD�+)

Noneornotsignificant >35 >30 >25 >500

Mild 30–35 25–30 20–25 350−499

Advanced 25–29 20–24 15−19 200−349

Severe <25 <20 <15 <200or<15%

Table �. WHO clinical staging of HIV/AIDS for adults and adolescents with confirmed HIV infection i

Clinical stage 1

AsymptomaticPersistentgeneralizedlymphadenopathy

Clinical stage 2

Moderateunexplainedweightloss(<10%ofpresumedormeasuredbodyweight)I

Recurrentrespiratorytractinfectionssinusitis,tonsillitis,otitismediaandpharyngitis)HerpeszosterAngularcheilitisRecurrentoralulcerationPapularpruriticeruptionsSeborrhoeicdermatitisFungalnailinfections

i Assessmentofbodyweightinpregnantwomanneedstoconsidertheexpectedweightgainofpregnancy.


Adults and adolescents iii

Clinical stage �

Unexplainedisevereweightloss(>10%ofpresumedormeasuredbodyweight)UnexplainedchronicdiarrhoeaforlongerthanonemonthUnexplainedpersistentfever(above37.6°Cintermittentorconstant, forlongerthanonemonth)PersistentoralcandidiasisOralhairyleukoplakiaPulmonarytuberculosis(current)Severebacterialinfections(suchaspneumonia,empyema,pyomyositis, boneorjointinfection,meningitisorbacteraemia)Acutenecrotizingulcerativestomatitis,gingivitisorperiodontitisUnexplainedanaemia(<8g/dl),neutropaenia(<0.5×109perlitre)orchronicthrombocytopaenia(<50×109perlitre)

Clinical stage �ii

HIVwastingsyndromePneumocystispneumoniaRecurrentseverebacterialpneumoniaChronicherpessimplexinfection(orolabial,genitaloranorectal

ofmorethanonemonth’sdurationorvisceralatanysite)Oesophagealcandidiasis(orcandidiasisoftrachea,bronchiorlungs)ExtrapulmonarytuberculosisKaposi’ssarcomaCytomegalovirusinfection(retinitisorinfectionofotherorgans)CentralnervoussystemtoxoplasmosisHIVencephalopathyExtrapulmonarycryptococcosisincludingmeningitisDisseminatednon-tuberculousmycobacterialinfectionProgressivemultifocalleukoencephalopathyChroniccryptosporidiosis(withdiarrhoed)ChronicisosporiasisDisseminatedmycosis(coccidiomycosisorhistoplasmosis)Recurrentnon-typhoidalSalmonellabacteraemiaLymphoma(cerebralorB-cellnon-Hodgkin)orothersolidHIV-associatedtumoursInvasivecervicalcarcinomaAtypicaldisseminatedleishmaniasisSymptomaticHIV-associatednephropathyorsymptomaticHIV-associatedcardiomyopathy

i Unexplainedreferstowheretheconditionisnotexplainedbyothercauses.

ii Someadditionalspecificconditionscanalsobeincludedinregionalclassifications(suchasreactivationofAmericantrypanoso-miasis[meningoencephalitisand/ormyocarditis])intheWHORegionoftheAmericasanddisseminatedpenicilliosisinAsia).

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Table �. WHO clinical staging of HIV/AIDS for children with confirmed HIV infection

Clinical stage 1

AsymptomaticPersistentgeneralizedlymphadenopathy

Clinical stage 2

UnexplainedpersistenthepatosplenomegalyPapularpruriticeruptionsFungalnailinfectionAngularcheilitisLinealgingivalerythemaExtensivewartvirusinfectionExtensivemolluscumcontagiosumRecurrentoralulcerationsUnexplainedpersistentparotidenlargementHerpeszosterRecurrentorchronicupperrespiratorytractinfections

(otitismedia,otorrhoea,sinusitisortonsillitis)

Clinical stage �

UnexplainedimoderatemalnutritionorwastingnotadequatelyrespondingtostandardtherapyUnexplainedpersistentdiarrhoea(14daysormore)Unexplainedpersistentfever(above37.5°Cintermittentorconstant,

forlongerthanonemonth)Persistentoralcandidiasis(afterfirst6–8weeksoflife)OralhairyleukoplakiaAcutenecrotizingulcerativegingivitisorperiodontitisLymphnodetuberculosisPulmonarytuberculosisSevererecurrentbacterialpneumoniaSymptomaticlymphoidinterstitialpneumonitisChronicHIV-associatedlungdiseaseincludingbrochiectasisUnexplainedanaemia(<8g/dl),neutropaenia(<0.5×109perlitre)

andorchronicthrombocytopaenia(<50×109perlitre)i

i Unexplainedreferstowheretheconditionisnotexplainedbyothercauses.


Children

Clinical stage �i

Unexplainedseverewasting,stuntingorseveremalnutritionnotrespondingtostandardtherapy

PneumocystispneumoniaRecurrentseverebacterialinfections(suchasempyema,pyomyositis,

boneorjointinfectionormeningitisbutexcludingpneumonia)Chronicherpessimplexinfection(orolabialorcutaneousofmorethanonemonth’s

durationorvisceralatanysite)Oesophagealcandidiasis(orcandidiasisoftrachea,bronchiorlungs)ExtrapulmonarytuberculosisKaposisarcomaCytomegalovirusinfection:retinitisorcytomegalovirusinfectionaffectinganotherorgan,

withonsetatageolderthanonemonthCentralnervoussystemtoxoplasmosis(afteronemonthoflife)Extrapulmonarycryptococcosis(includingmeningitis)HIVencephalopathyDisseminatedendemicmycosis(coccidiomycosisorhistoplasmosis)Disseminatednon-tuberculousmycobacterialinfectionChroniccryptosporidiosis(withdiarrhoed)ChronicisosporiasisCerebralorB-cellnon-HodgkinlymphomaProgressivemultifocalleukoencephalopathySymptomaticHIV-associatednephropathyorHIV-associatedcardiomyopathy

i

i Someadditionalspecificconditionscanalsobeincludedinregionalclassifications(suchasreactivationofAmericantrypano-somiasis[meningoencephalitisand/ormyocarditis]intheWHORegionoftheAmericas,disseminatedpenicilliosisinAsiaandHIV-associatedrectovaginalfistulainAfrica).

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CRITERIA FOR HIV STAGING EVENTS Adults (1� years or older)

Clinical event Clinical diagnosis Definitive diagnosis

Clinical stage 1

Asymptomatic. NoHIV-relatedsymptomsreportedandnosignsonexamination.

Notapplicable.

Persistentgeneralizedlymphadenopathy.

Painlessenlargedlymphnodes>1cmintwoormorenon-contiguoussites(excludinginguinal)intheabsenceofknowncauseandpersistingforthreemonthsormore.

Histology.

Clinical stage 2

Unexplainedmoderateweightloss(<10%ofbodyweight).

Reportedunexplainedinvoluntaryweightlossinpregnancyfailuretogainweight.

Documentedweightloss<10%ofbodyweight.

Recurrentupperrespiratorytractinfections(currenteventplusoneormoreinlastsix-monthperiod).

Symptomcomplex,suchasunilateralfacepainwithnasaldischarge(sinusitis),painfulinflamedeardrum(otitismedia)ortonsillopharyngitiswithoutfeaturesofviralinfection(suchascoryzaorcough).

Laboratorystudieswhereavailable,suchascultureofsuitablebodyfluid.

Herpeszoster. Painfulvesicularrashindermatomaldistributionofanervesupply,doesnotcrossthemidline.

Clinicaldiagnosis.

Angularcheilitis. Splitsorcracksattheangleofthemouthnotduetoironorvitamindeficiency,usuallyrespondtoantifungaltreatment.

Clinicaldiagnosis.

ANNEx 1. pRESUMpTIVE AND DEFINITIVE CRITERIA FOR RECOGNIzING HIV-RELATED CLINICAL EVENTS IN ADULTS (15 yEARS OR OLDER) AND CHILDREN (yOUNGER THAN 15 yEARS) WITH CONFIRMED HIV INFECTION



Recurrentoralulceration(twoormoreepisodesinlastsixmonths).

Aphthousulceration,typicallypainfulwithahaloofinflammationandayellow-greypseudomembrane.

Clinicaldiagnosis.

Papularpruriticeruption. Papularpruriticlesions,oftenwithmarkedpost-inflammatorypigmentation.

Clinicaldiagnosis.

Seborrhoeicdermatitis. Itchyscalyskincondition,particularlyaffectinghairyareas(scalp,axillae,uppertrunkandgroin).

Clinicaldiagnosis.

Fungalnailinfection. Paronychia(painfulredandswollennailbed)oronycholysis(separationofthenailfromthenailbed)ofthefingernails(whitediscoloration–especiallyinvolvingproximalpartofnailplate–withthickeningandseparationofthenailfromthenailbed).

Fungalcultureofthenailornailplatematerial.

Clinical stage �

Unexplainedsevereweightloss(morethan10%ofbodyweight).

Reportedunexplainedinvoluntaryweightloss(>10%ofbodyweight)andvisiblethinningofface,waistandextremitieswithobviouswastingorbodymassindex<18.5kg/m2;inpregnancy,theweightlossmaybemasked.

Documentedlossofmorethan10%ofbodyweight.

Adults (1� years or older)

21


Unexplainedchronicdiarrhoeaforlongerthanonemonth.

Chronicdiarrhoea(looseorwaterystoolsthreeormoretimesdaily)reportedforlongerthanonemonth.

Threeormorestoolsobservedanddocumentedasunformed,andtwoormorestooltestsrevealnopathogens.

Unexplainedpersistentfever(intermittentorconstantandlastingforlongerthanonemonth).

Feverornightsweatsformorethanonemonth,eitherintermittentorconstantwithreportedlackofresponsetoantibioticsorantimalarialagents,withoutotherobviousfociofdiseasereportedorfoundonexamination;malariamustbeexcludedinmalariousareas.

Documentedfever>37.5°Cwithnegativebloodculture,negativeZiehl-Nielsenstain,negativemalariaslide,normalorunchangedchestX-rayandnootherobviousfocusofinfection.

Persistantoralcandidiasis. Persistentorrecurringcreamywhitecurd-likeplaquesthatcanbescrapedoff(pseudomembranous)orredpatchesontongue,palateorliningofmouth,usuallypainfulortender(erythematousform).

Clinicaldiagnosis.

Oralhairyleukoplakia. Finewhitesmalllinearorcorrugatedlesionsonlateralbordersofthetonguethatdonotscrapeoff.

Clinicaldiagnosis.




Pulmonarytuberculosis(current).

Chronicsymptoms:(lastingatleast2–3weeks)cough,haemoptysis,shortnessofbreath,chestpain,weightloss,fever,nightsweats;

PLUSEITHER

positivesputumsmear;

OR

negativesputumsmear;

AND

compatiblechestradiograph(includingbutnotrestrictedtoupperlobeinfiltrates,caritation,pulmonaryfibrosistshrinkage.

Noevidenceofextrapulmonarydiseas.

IsolationofM. Tuberculosis onsputumcultureorhistologyoflungbiopsy(withcompatiblesymptoms).

Severebacterialinfection(suchaspneumonia,meningitis,empyema,pyomyositis,boneorjointinfection,bacteraemiaandseverepelvicinflammatorydisease).

Feveraccompaniedbyspecificsymptomsorsignsthatlocalizeinfectionandresponsetoappropriateantibiotic.

Isolationofbacteriafromappropriateclinicalspecimens(usuallysterilesites).

Acutenecrotizingulcerativegingivitisornecrotizingulcerativeperiodontitis.

Severepain,ulceratedgingivalpapillae,looseningofteeth,spontaneousbleeding,badodourandrapidlossofboneand/orsofttissue.

Clinicaldiagnosis.


2�


Unexplainedanaemia(<8g/dl),neutropaenia(<0.5×109perlitre)orchronic(morethanonemonth)thrombocytopaenia(<50×109perlitre).

Notpresumptiveclinicaldiagnosis.

Diagnosedonlaboratorytestingandnotexplainedbyothernon-HIVconditions;notrespondingtostandardtherapywithhaematinics,antimalarialagentsoranthelminticagentsasoutlinedinrelevantnationaltreatmentguidelines,WHOIntegratedManagementofChildhoodIllnessguidelinesorotherrelevantguidelines.

Clinical stage �

HIVwastingsyndrome. Unexplainedinvoluntaryweightloss(>10%baselinebodyweight),withobviouswastingorbodymassindex<18.5;

PLUSEITHER

unexplainedchronicdiarrhoea(looseorwaterystoolsthreeormoretimesdaily)reportedforlongerthanonemonth;

OR

reportsoffeverornightsweatsformorethanonemonthwithoutothercauseandlackofresponsetoantibioticsorantimalarialagents;malariamustbeexcludedinmalariousareas.

Documentedweightloss(>10%ofbodyweight);

PLUSEITHER

twoormoreunformedstoolsnegativeforpathogens;

OR

documentedtemperatureof>37.5°Cwithnoothercauseofdisease,negativebloodculture,negativemalariaslideandnormalorunchangedchestX-ray.




Pneumocystispneumonia. Dyspnoeaonexertionornonproductivecoughofrecentonset(withinthepastthreemonths),tachypnoeaandfever;

AND

ChestX-rayevidenceofdiffusebilateralinterstitialinfiltrates;

AND

Noevidenceofbacterialpneumonia;bilateralcrepitationsonauscultationwithorwithoutreducedairentry.

Cytologyorimmunofluorescentmicroscopyofinducedsputumorbronchoalveolarlavageorhistologyoflungtissue.

Recurrentbacterialpneumonia;

(thisepisodeplusoneormoreepisodesinlastsixmonths).

Currentepisodeplusoneormorepreviousepisodesinthepastsixmonths;acuteonset(<2weeks)ofseveresymptoms(suchasfever,cough,dyspnoea,andchestpain)PLUSnewconsolidationonclinicalexaminationorchestX-ray;responsetoantibiotics.

Positivecultureorantigentestofacompatibleorganism.

Chronicherpessimplexvirusinfection(orolabial,genitaloranorectal)ofmorethanonemonthorvisceralinfectionofanyduration.

Painful,progressiveanogenitalororolabialulceration;lesionscausedbyrecurrenceofherpessimplexvirusinfectionandreportedformorethanonemonth.Historyofpreviousepisodes.Visceralherpessimplexvirusrequiresdefinitivediagnosis.

PositivecultureorDNA(bypolymerasechainreaction)ofherpessimplexvirusorcompatiblecytologyorhistology.


2�


Oesophagealcandidiasis. Recentonsetofretrosternalpainordifficultyonswallowing(foodandfluids)togetherwithoralcandidasis.

Macroscopicappearanceatendoscopyorbronchoscopy,orbymicroscopyorhistology.

Extrapulmonarytuberculosis. Systemicillness(suchasfever,nightsweats,weaknessandweightloss).Otherevidenceforextrapulmonaryordisseminatedtuberculosisvariesbysite:Pleural,pericardia,peritonealinvolvement,meningitis,mediastinalorabdominallymphadenopathyorostetis.

DiscreteperipherallymphnodeMycobacteriumtuberculosisinfection(especiallycervical)isconsideredalesssevereformofextrapulmonarytuberculosis.

M. tuberculosisisolationorcompatiblehistologyfromappropriatesiteorradiologicalevidenceofmiliarytuberculosis;

(diffuseuniformlydistributedsmallmiliaryshadowsormicronodulesonchestX-ray).

Kaposisarcoma. Typicalgrossappearanceinskinororopharynxofpersistent,initiallyflat,patcheswithapinkorviolaceouscolour,skinlesionsthatusuallydevelopintoplaquesornodules.

Macroscopicappearanceatendoscopyorbronchoscopy,orbyhistology.




Cytomegalovirusdisease(otherthanliver,spleenorlymphnode).

Retinitisonly:maybediagnosedbyexperiencedclinicians.Typicaleyelesionsonfundoscopicexamination:discretepatchesofretinalwhiteningwithdistinctborders,spreadingcentrifugally,oftenfollowingbloodvessels,associatedwithretinalvasculitis,haemorrhageandnecrosis.

CompatiblehistologyorcytomegalovirusdemonstratedincerebrospinalfluidbycultureorDNA(bypolymerasechainreaction).

Centralnervoussystemtoxoplasmosis.

RecentonsetofafocalnervoussystemabnormalityconsistentwithintracranialdiseaseorreducedlevelofconsciousnessANDresponsewithin10daystospecifictherapy.

PositiveserumtoxoplasmaantibodyAND(ifavailable)singleormultipleintracranialmasslesiononneuroimaging(computedtomographyormagneticresonanceimaging).

HIVencephalopathy. Disablingcognitiveand/ormotordysfunctioninterferingwithactivitiesofdailyliving,progressingoverweeksormonthsintheabsenceofaconcurrentillnessorconditionotherthanHIVinfectionthatmightexplainthefindings.

Diagnosisofexclusion:and(ifavailable)neuroimaging(computedtomographyormagneticresonanceimaging).

Extrapulmonarycryptococcosis(includingmeningitis).

Meningitis:usuallysubacute,feverwithincreasingsevereheadache,meningism,confusion,behaviouralchangesthatrespondtocryptococcaltherapy.

IsolationofCryptococcus neoformansfromextrapulmonarysiteorpositivecryptococcalantigentestoncerebrospinalfluidorblood.


2�


Disseminatednon-tuberculousmycobacteriainfection.

Nopresumptiveclinicaldiagnosis.

Diagnosedbyfindingatypicalmycobacterialspeciesfromstool,blood,bodyfluidorotherbodytissue,excludingthelungs.

Progressivemultifocalleukoencephalopathy.


Progressivenervoussystemdisorder(cognitivedysfunction,gait/speechdisorder,visualloss,limbweaknessandcranialnervepalsies)togetherwithhypodensewhitematterlesionsonneuro-imagingorpositivepolyomavirusJCpolymerasechainreactiononcerebrospinalfluid.

Chroniccryptosporidiosis(withdiarrhoealastingmorethanonemonth).


CystsidentifiedonmodifiedZiehl-Nielsenstainmicroscopicexaminationofunformedstool.

Chronicisosporiasis. Nopresumptiveclinicaldiagnosis.

IdentificationofIsospora.

Disseminatedmycosis(coccidiomycosisorhistoplasmosis).


Histology,antigendetectionorculturefromclinicalspecimenorbloodculture.

Recurrentnon-typhoidSalmonellabacteraemia.


Bloodculture.

Lymphoma(cerebralorB-cellnon-Hodgkin).


Histologyofrelevantspecimenor,forcentralnervoussystemtumours,neuroimagingtechniques.

Invasivecervicalcarcinoma. Nopresumptiveclinicaldiagnosis.

Histologyorcytology.




Atypicaldisseminatedleishmaniasis.


Diagnosedbyhistology(amastigotesvisualized)orculturefromanyappropriateclinicalspecimen.

SymptometicHIV-associatednephropathy.


Renalbiopsy.

SymptometicHIV-associatedcardiomyopathy.


Cardiomegalyandevidenceofpoorleftventricularfunctionconfirmedbyechocardiography.


2�

CRITERIA FOR WHO CLINICAL STAGING EVENTS Children (younger than 1� years)


Clinical stage 1

Asymptomatic. NoHIV-relatedsymptomsreportedandnoclinicalsignsonexamination.

Notapplicable.

Persistentgeneralizedlymphadenopathy.

Persistentenlargedlymphnodes>1cmattwoormorenon-contiguoussites(excludinginguinal)withoutknowncause.

Clinicaldiagnosis.

Clinical stage 2

Unexplainedpersistenthepatosplenomegaly.

Enlargedliverandspleenwithoutobviouscause.

Clinicaldiagnosis.

Papularpruriticeruptions. Papularpruriticvesicularlesions.

Clinicaldiagnosis.

Fungalnailinfections. Fungalparonychia(painful,redandswollennailbed)oronycholysis(painlessseparationofthenailfromthenailbed).Proximalwhitesubungualonchomycosisisuncommonwithoutimmunodeficiency.

Clinicaldiagnosis.

Angularcheilitis. Splitsorcracksattheangleofthemouthnotattributabletoironorvitamindeficiency,andusuallyrespondingtoantifungaltreatment.

Clinicaldiagnosis.

Linealgingivalerythema. Erythematousbandthatfollowsthecontourofthefreegingivalline;maybeassociatedwithspontaneousbleeding.

Clinicaldiagnosis.

�0 WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN


Extensivewartvirusinfection.

Characteristicwartyskinlesions;smallfleshygrainybumps,oftenrough,flatonsoleoffeet(plantarwarts);facial,morethan5%ofbodyareaordisfiguring.

Clinicaldiagnosis.

Extensivemolluscumcontagiosuminfection.

Characteristicskinlesions:smallflesh-coloured,pearlyorpink,dome-shapedorumbilicatedgrowthsmaybeinflamedorred;facial,morethan5%ofbodyareaordisfiguring.Giantmolluscummayindicatemoreadvancedimmunodeficiency.

Clinicaldiagnosis.

Recurrentoralulceration. Currenteventplusatleastonepreviousepisodeinpastsixmonths.Aphthousulceration,typicallywithahaloofinflammationandyellow-greypseudomembrane.

Clinicaldiagnosis.

Unexplainedpersistentparotidenlargement.

Asymptomaticbilateralswellingthatmayspontaneouslyresolveandrecur,inabsenceofotherknowncause,usuallypainless.

Clinicaldiagnosis.

Herpeszoster. Painfulrashwithfluid-filledblisters,dermatomaldistribution,canbehaemorrhagiconerythematousbackground,andcanbecomelargeandconfluent.Doesnotcrossthemidline.

Clinicaldiagnosis.

Children (younger than 1� years)

�1


Recurrentorchronicupperrespiratorytractinfection.

Currenteventwithatleastoneepisodeinthepastsixmonths.Symptomcomplex;feverwithunilateralfacepainandnasaldischarge(sinusitis)orpainfulswolleneardrum(otitismedia),sorethroatwithproductivecough(bronchitis),sorethroat(pharyngitis)andbarkingcroup-likecough(laryngotrachealbronchitis).Persistentorrecurrenteardischarge.

Clinicaldiagnosis.

Clinical stage �

Unexplainedmoderatemalnutritionorwasting.

Weightloss:lowweight-for-age,upto−2standarddeviationsfromthemean,notexplainedbypoororinadequatefeedingandorotherinfections,andnotadequatelyrespondingtostandardmanagement.

Documentedlossofbodyweightof–2standarddeviationsfromthemean,failuretogainweightonstandardmanagementandnoothercauseidentifiedduringinvestigation.

Unexplainedpersistentdiarrhoea.

Unexplainedpersistent(14daysormore)diarrhoea(looseorwaterystool,threeormoretimesdaily),notrespondingtostandardtreatment.

Stoolsobservedanddocumentedasunformed.Cultureandmicroscopyrevealnopathogens.




Unexplainedpersistentfever;

(>37.5°Cintermittentorconstantforlongerthanonemonth).

Reportsoffeverornightsweatsforlongerthanonemonth,eitherintermittentorconstant,withreportedlackofresponsetoantibioticsorantimalarialagents.Nootherobviousfociofdiseasereportedorfoundonexamination.Malariamustbeexcludedinmalariousareas.

Documentedfeverof>37.5°Cwithnegativebloodculture,negativemalariaslideandnormalorunchangedchestX-rayandnootherobviousfociofdisease.

Oralcandidiasis;

(afterthefirst6–8weeksoflife).

Persistentorrecurringcreamywhitetoyellowsoftsmallplaqueswhichcanbescrapedoff(pseudomembranous),orredpatchesontongue,palateorliningofmouth,usuallypainfulortender(erythematousform).

Microscopyorculture.

Oralhairyleukoplakia. Finesmalllinearpatchesonlateralbordersoftongue,generallybilaterally,thatdonotscrapeoff.

Clinicaldiagnosis.

Acutenecrotizingulcerativegingivitisorstomatitis,oracutenecrotizingulcerativeperiodontitis.

Severepain,ulceratedgingivalpapillae,looseningofteeth,spontaneousbleeding,badodour,andrapidlossofboneand/orsofttissue.

Clinicaldiagnosis.

Lymphnodetuberculosis. Non-acute,painless“cold”enlargementofperipherallymphnodes,localizedtooneregion.Responsetostandardantituberculosistreatmentinonemonth.

HistologyorfineneedleaspiratepositiveforZiehl-Nielsenstainorculture.


��


Pulmonarytuberculosis. Nonspecificsymptoms,suchaschroniccough,fever,nightsweats,anorexiaandweightloss.Intheolderchildalsoproductivecoughandhaemoptysis.Historyofcontactwithadultswithsmear-positivepulmonarytuberculosis.Noresponsetostandardbroad-spectrumantibiotictreatment.

Oneormoresputumsmearpositiveforacid-fastbacilliand/orradiographicabnormalitiesconsistentwithactivetuberculosisand/orculture-positiveforMycobacterium.

Severerecurrentbacterialpneumonia.

Coughwithfastbreathing,chestindrawing,nasalflaring,wheezing,andgrunting.Cracklesorconsolidationonauscultation.Respondstocourseofantibiotics.Currentepisodeplusoneormoreinprevioussixmonths.

Isolationofbacteriafromappropriateclinicalspecimens(inducedsputum,bronchoalveolarlavageandlungaspirate).

Symptomaticlymphocyticinterstitialpneumonia.


ChestX-ray:bilateralreticulonodularinterstitialpulmonaryinfiltratespresentformorethantwomonthswithnoresponsetoantibiotictreatmentandnootherpathogenfound.Oxygensaturationpersistently<90%.Corpulmonaleandincreasedexercise-inducedfatigue.Characteristichistology.

ChronicHIV-associatedlungdisease(includingbronchiectasis).

Historyofcoughproductiveofcopiousamountsofpurulentsputum(bronchiectasisonly),withorwithoutclubbing,halitosis,andcrepitationsand/orwheezesonauscultation.

ChestX-raymayshowhoneycombappearance(smallcysts)and/orpersistentareasofopacificationand/orwidespreadlungdestruction,withfibrosisandlossofvolume.


�� WHO CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN


Unexplainedanaemia(<8g/dl),neutropaenia(<0.5×109perlitre)andorchronicthrombocytopaenia(<50×109perlitre).


Laboratorytesting,notexplainedbyothernon-HIVconditions,notrespondingtostandardtherapywithhaematinics,antimalarialagentsoranthelminticagentsasoutlinedinWHOIntegratedManagementofChildhoodIllnessguidelines.

Clinical stage �

Unexplainedseverewasting,stuntingorseveremalnutritionnotadequatelyrespondingtostandardtherapy.

Persistentweightlossstuntingwastingormalnutritionnotexplainedbypoororinadequatefeeding,otherinfectionsandnotadequatelyrespondingintwoweekstostandardtherapy.Visibleseverewastingofmuscles,withorwithoutoedemaofbothfeet,and/orweight-for-heightof–3standarddeviationsfromthemean,asdefinedbyWHOIntegratedManagementofChildhoodIllnessguidelines.

Documentedweightforheightorweightforageofmorethan–3standarddeviationsfromthemeanwithorwithoutoedema.


��


Pneumocystispneumonia. Drycough,progressivedifficultyinbreathing,cyanosis,tachypnoeaandfever;chestindrawingorstridor.(SevereorveryseverepneumoniaasinWHOIntegratedManagementofChildhoodIllnessguidelines.)Rapidonsetespeciallyininfantsyoungerthansixmonthsofage.Responsetohigh-doseco-trimoxazolewithorwithoutprednisolone.ChestX-rayshowstypicalbilateralperihilardiffuseinfiltrates.

Cytologyorimmunofluorescentmicroscopyofinducedsputumorbronchoalveolarlavageorhistologyoflungtissue.

Recurrentseverebacterialinfection,suchasempyema,pyomyositis,boneorjointinfectionormeningitisbutexcludingpneumonia.

Feveraccompaniedbyspecificsymptomsorsignsthatlocalizeinfection.Respondstoantibiotics.Currentepisodeplusoneormoreinprevioussixmonths.

Cultureofappropriateclinicalspecimen.

Chronicherpessimplexinfection;(orolabialorcutaneousofmorethanonemonth’sdurationorvisceralatanysite).

Severeandprogressivepainfulorolabial,genital,oranorectallesionscausedbyherpessimplexvirusinfectionpresentformorethanonemonth.

Cultureand/orhistology.

Oesophagealcandidiasis;

(orcandidiasisoftrachea,bronchiorlungs).

Difficultyinswallowing,orpainonswallowing(foodandfluids).Inyoungchildren,suspectparticularlyiforalCandidaobservedandfoodrefusaloccursand/ordifficultyorcryingwhenfeeding.

Macroscopicappearanceatendoscopy,microscopyofspecimenfromtissueormacroscopicappearanceatbronchoscopyorhistology.




Extrapulmonarytuberculosis. Systemicillnessusuallywithprolongedfever,nightsweatsandweightloss.Clinicalfeaturesoforgansinvolved,suchassterilepyuria,pericarditis,ascites,pleuraleffusion,meningitis,arthritis,orchitis,pericardialorabdominal.

Positivemicroscopyshowingacid-fastbacilliorcultureofMycobacteriumtuberculosisfrombloodorotherrelevantspecimenexceptsputumorbronchoalveolarlavage.Biopsyandhistology.

Kaposisarcoma. Typicalappearanceinskinororopharynxofpersistent,initiallyflat,patcheswithapinkorblood-bruisecolour,skinlesionsthatusuallydevelopintonodules.

Macroscopieappearenceorbyhistology.

Cytomegalovirusretinitisorcytomegalovirusinfectionaffectinganotherorgan,withonsetatageolderthanonemonth.

Retinitisonly.

Cytomegalovirusretinitismaybediagnosedbyexperiencedclinicians:typicaleyelesionsonserialfundoscopicexamination;discretepatchesofretinalwhiteningwithdistinctborders,spreadingcentrifugally,oftenfollowingbloodvessels,associatedwithretinalvasculitis,haemorrhageandnecrosis.

Definitivediagnosisrequiredforothersites.Histologyorcytomegalovirusdemonstratedincerebrospinalfluidbypolymerasechainreaction.

Centralnervoussystemtoxoplasmosisonsetafterageonemonth.

Fever,headache,focalnervoussystemsignsandconvulsions.Usuallyrespondswithin10daystospecifictherapy.

Computedtomographyscan(orotherneuroimaging)showingsingleormultiplelesionswithmasseffectorenhancingwithcontrast.


��


Extrapulmonarycryptococcosis(includingmeningitis).

Meningitis:usuallysubacute,feverwithincreasingsevereheadache,meningism,confusionandbehaviouralchangesthatrespondtocryptococcaltherapy.

Cerebrospinalfluidmicroscopy(IndiainkorGramstain),serumorcerebrospinalfluidcryptococcalantigentestorculture.

HIVencephalopathy. Atleastoneofthefollowing,progressingoveratleasttwomonthsintheabsenceofanotherillness:

failuretoattain,orlossof,developmentalmilestonesorlossofintellectualability;

OR

progressiveimpairedbraingrowthdemonstratedbystagnationofheadcircumference;

OR

acquiredsymmetricalmotordeficitaccompaniedbytwoormoreofthefollowing:paresis,pathologicalreflexes,ataxiaandgaitdisturbances.

Neuroimagingdemonstratingatrophyandbasalgangliacalcificationandexcludingothercauses.

Disseminatedmycosis(coccidiomycosisorhistoplasmosis).


Histology:usuallygranulomaformation.

Isolation:antigendetectionfromaffectedtissue;cultureormicroscopyfromclinicalspecimenorbloodculture.




Disseminatedmycobacteriosis,otherthantuberculosis.


Nonspecificclinicalsymptomsincludingprogressiveweightloss,fever,anaemia,nightsweats,fatigueordiarrhoea;pluscultureofatypicalmycobacterialspeciesfromstool,blood,bodyfluidorotherbodytissue,excludingthelung.

Chroniccryptosporidiosis;

(withdiarrhoea).


CystsidentifiedonmodifiedZiehl-Nielsenmicroscopicexaminationofunformedstool.

ChronicIsosporiasis. Nopresumptiveclinicaldiagnosis.

IdentificationofIsospora.

CerebralorB-cellnon-Hodgkinlymphoma.


Diagnosedbycentralnervoussystemneuroimaging;histologyofrelevantspecimen.

Progressivemultifocalleukoencephalopathy.


Progressivenervoussystemdisorder(cognitivedysfunction,gaitorspeechdisorder,visualloss,limbweaknessandcranialnervepalsies)togetherwithhypodensewhitematterlesionsonneuroimagingorpositivepolyomavirusJC(JCV)polymerasechainreactiononcerebrospinalfluid.

SymptomaticHIV-associatednephropathy.


Renalbiopsy.

SymptomaticHIV-associatedcardiomyopathy.


Cardiomegalyandevidenceofpoorleftventricularfunctionconfirmedbyechocardiography.


3�

Clinical criteria for presumptive diagnosis of severe HIV disease among infants and children aged under 1� months in situations where

virological testing is not available

A presumptive diagnosis of severe HIV disease should be made if:• the infant is confirmed as HIV antibody-positive;

and

• diagnosis of any AIDS-indicator condition(s)a can be made;

or

• the infant is symptomatic with two or more of the following;

oral thrushb; severe pneumoniab; severe sepsisb.

Other factors that support the diagnosis of severe HIV disease in an HIV-seropositive infant include:

• recent HIV-related maternal death or advanced HIV disease in the mother;

• CD4 <20%.c

Confirmation of the diagnosis of HIV infection should be sought as soon as possible.

a AIDS indicator conditions include some but not all HIV clinical stage 4 conditions seen in children such as Pneumocystis pneu-monia, oesophageal candidiasis, cryptococcal meningitis, cerebral toxoplasmosis, unexplained wasting or malnutrition.

b Defined in accordance with WHO Integrated Management of Childhood Illness guidelines:• Oral thrush: Creamy white soft small plaques on red or normally coloured mucosa which can often be scraped off (pseudomem-

branous), or red patches on tongue, palate or lining of mouth, usually painful or tender.• Severe pneumonia: Cough or difficult breathing in a child with chest indrawing, stridor or any of the general danger signs

outlined in the WHO Integrated Management of Childhood Illness guidelines: that is lethargic or unconscious, not able to drink or breastfeed, vomiting and presence or history of convulsions during current illness,.

• Severe sepsis: Fever or low body temperature in a young infant with any severe sign, such as rapid breathing, chest indrawing, bulging fontanelle, lethargy, reduced movement, not feeding or sucking breast-milk, convulsions, stiff neck.

c It is unclear how often the CD4 count is lowered in these conditions in HIV-uninfected children.

annex 2. presumptiVe diagnOsis Of seVere HiV disease in infants


[1] WorldHealthOrganization.WorkshoponAIDSinAfrica1986(WHO/CDS/AIDS.85.1).

[2] WorldHealthOrganization.AcquiredImmunodeficiencysyndrome(AIDS)WHO/CDCcasedefinitionforsurveillanceWeeklyEpidemiologicalRecord.19867March(10).

[3] WorldHealthOrganization.AcquiredImmunodeficiencySyndrome.1987RevisionofWHO/CDCcasedefinitionforAIDS.WeeklyEpidemiologicalRecord.19881-8January;63:1-8.

[4] RevisionoftheCDCsurveillancecasedefinitionforacquiredimmunodeficiencysyndrome.Council of State and Territorial Epidemiologists; AIDS Program, Center for InfectiousDiseases.MMWRMorbMortalWklyRep.1987Aug14;36Suppl1:1S-15S.

[5] Revision of CDC/WHO case definition for acquired immunodeficiency syndrome (AIDS).BullPanAmHealthOrgan.1988;22(2):195-201.

[6] WorldHealthOrganization.AIDS:1987 revisionofCDC/WHOcasedefinition.BullWorldHealthOrgan.1988;66(2):259-63,69-73.

[7] World Health Organization. WHO case definitions for AIDS surveillance in adults andadolescentsWeeklyEpidemiologicalRecord.199416September;69:273.

[8] EuropeanAIDScasedefinition.CommunDisRepCDRWkly.1993Jul30;3(31):141.

[9] Effectofthe1993EuropeanAIDScasedefinitionintheUnitedKingdom.CommunDisRepCDRWkly.1994Jan14;4(2):5.

[10] DownsAM,HeisterkampSH,RavaL,HouwelingH,JagerJC,HamersFF.Back-calculationbybirthcohort, incorporatingage-specificdiseaseprogression,pre-AIDSmortalityandchangeinEuropeanAIDScasedefinition.EuropeanUnionConcertedActiononMultinationalAIDSScenarios.AIDS.2000Sep29;14(14):2179-89.

[11] PezzottiP,NapoliPA,RezzaG,LazzeriV,AcciaiS,CuriaR,etal.Theeffectof the1993European revisionof theAIDScasedefinition in Italy: implications formodelling theHIVepidemic.AIDS.1997Jan;11(1):95-9.

[12] VerdecchiaA,GrossiP,CantoniM.Theimpactofthe1993EuropeanrevisionoftheAIDScasedefinitiononback-calculationestimates:anapplicationinItaly.EurJEpidemiol.1998Jul;14(5):427-32.

[13] ChintuC,MalekA,NyumbuM,LuoC,MasonaJ,DuPontHL,etal.Casedefinitions forpaediatricAIDS:theZambianexperience.IntJSTDAIDS.1993Mar-Apr;4(2):83-5.

[14] KeouFX,BelecL,EsungePM,CancreN,GresenguetG.WorldHealthOrganizationclinicalcase definition for AIDS in Africa: an analysis of evaluations. East Afr Med J. 1992Oct;69(10):550-3.

[15] LepageP,vandePerreP,DabisF,CommengesD,OrbinskiJ,HitimanaDG,etal.Evaluationandsimplificationof theWorldHealthOrganizationclinical casedefinition forpaediatricAIDS.AIDS.1989Apr;3(4):221-5.

REFERENCES

�1

[16] Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA, 3rd, et al.Triple-nucleosideregimensversusefavirenz-containingregimensfortheinitialtreatmentofHIV-1infection.NEnglJMed.2004Apr29;350(18):1850-61.

[17] RouetF,ElengaN,MsellatiP,MontchoC,VihoI,SakarovitchC,etal.PrimaryHIV-1infectioninAfricanchildreninfectedthroughbreastfeeding.AIDS.2002Nov22;16(17):2303-9.

[18] MesseleT,BrouwerM,GirmaM,FontanetAL,MiedemaF,HamannD,etal.Plasmalevelsofviro-immunologicalmarkersinHIV-infectedandnon-infectedEthiopians:correlationwithcellsurfaceactivationmarkers.ClinImmunol.2001Feb;98(2):212-9.

[19] DeRossiA.PrimaryHIVinfectionininfants:impactofhighlyactiveantiretroviraltherapyonthenaturalcourse.JBiolRegulHomeostAgents.2002Jan-Mar;16(1):53-7.

[20] KramerAB,R.J.Hampl,H.Friedman,R.M.Fuchs,D.Wachter,H.Goedert,J.J.Immunologicmarkersofprogressiontoacquiredimmunodeficiencysyndromearetime-dependentandillness-specific.AmJEpidemiol.1992Jul1;136(1):71-80(0002-9262).

[21] SmithGH,BoulasselMR,KlienM,GilmoreN,MacLeodJ,LeBlancR,etal.Virologicandimmunologic response to a boosted double-protease inhibitor-based therapy in highlypretreatedHIV-1-infectedpatients.HIVClinTrials.2005Mar-Apr;6(2):63-72.

[22] Soogoor M, Daar ES. Primary HIV-1 Infection: Diagnosis, Pathogenesis, and Treatment.CurrInfectDisRep.2005Mar;7(2):147-53.

[23] Kassutto S, Rosenberg ES. Primary HIV type 1 infection. Clin Infect Dis. 2004 May15;38(10):1447-53.

[24] WorldHealthOrganization. Interimproposal foraWHOStagingSystemforHIV infectionanddisease.WeeklyEpidemiologicalRecord.199020July65(29).

[25] World Health Organization. SCALING UP ANTIRETROVIRAL THERAPY IN RESOURCE-LIMITEDSETTINGS:TREATMENTGUIDELINESFORAPUBLICHEALTHAPPROACH.2003

[26] CDC. 1994 Revised classification system for human immunodeficiency virus infection inchildren<13yearsofage.MMWR1994;43(RR-12).

[27] BadriM,MaartensG,WoodR.Predictorsandprognosticvalueoforalhairy leukoplakiaand oral candidiasis in South African HIV-infected patients. South African Journal. 2001Dec;56(12):592-6.

[28] CampoJ,DelRomeroJ,CastillaJ,GarciaS,RodriguezC,BasconesA.Oralcandidiasisas a clinical marker related to viral load, CD4 lymphocyte count and CD4 lymphocytepercentageinHIV-infectedpatients.JOralPatholMed.2002Jan;31(1):5-10.

[29] DilysMorganCM,BillyMayanja,JamesAGWhitworth.Progressiontosymptomaticdiseasein people infected with HIV1 in rural Uganda: prospective cohort study. British MedicalJournal.2002Jan324:193–7.


[30] Dunn D. Short-term risk of disease progression in HIV-1-infected children receiving noantiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet. 2003 Nov15;362(9396):1605-11.

[31] Fahey J, Taylor JM, Detels R, Hofmann B, Melmed R, Nishanian P, Giorgi JV, et al. Theprognosticvalueofcellularandserologicmarkersininfectionwithhumanimmunodeficiencyvirustype1.N.EnglJMed.1990Jun28;322(26):1886.

[32] FrenchN,MujugiraA,NakiyingiJ,MulderD,JanoffEN,GilksCF.ImmunologicandclinicalstagesinHIV-1-infectedUgandanadultsarecomparableandprovidenoevidenceofrapidprogressionbutpoorsurvivalwithadvanceddisease.JAcquirImmuneDeficSyndr.1999Dec15;22(5):509-16.

[33] MalambaSSM,D.Clayton,T.Mayanja,B.Okongo,M.Whitworth,J.Theprognosticvalueof the World Health Organisation staging system for HIV infection and disease in ruralUganda.1999;AIDS(13):2555-62.

[34] SteinDS,LylesRH,GrahamNM,TassoniCJ,MargolickJB,PhairJP,etal.Predictingclinicalprogression or death in subjects with early-stage human immunodeficiency virus (HIV)infection: a comparative analysis of quantification of HIV RNA, soluble tumor necrosisfactortypeIIreceptors,neopterin,andbeta2-microglobulin.MulticenterAIDSCohortStudy.JInfectDis.1997Nov;176(5):1161-7.

[35] WhittleHEgbogaA,ToddJ,CorrahT,WilkinsA,DembaE,MorganG,etal.Clinicalandlaboratory predictors of survival in Gambian patients with symptomatic HIV-1 or HIV-2infection.AIDS1992Jul;6(7):685-9.

[36] MellorsJW,MunozA,GiorgiJV,MargolickJB,TassoniCJ,GuptaP,etal.PlasmaviralloadandCD4+lymphocytesasprognosticmarkersofHIV-1infection.AnnInternMed.1997Jun15;126(12):946-54.

[37] BonnetF,ThiebautR,CheneG,NeauD,PellegrinJL,MercieP,etal.Determinantsofclinicalprogression in antiretroviral-naive HIV-infected patients starting highly active antiretroviraltherapy.AquitaineCohort,France,1996-2002.HIVMed.2005May;6(3):198-205.

[38] TahaTE,GrahamSM,KumwendaNI,BroadheadRL,HooverDR,MarkakisD,etal.Morbidityamong human immunodeficiency virus-1-infected and -uninfected African children.Pediatrics.2000Dec;106(6):E77.

[39] O’BrienWA,HartiganPM,DaarES,SimberkoffMS,HamiltonJD.ChangesinplasmaHIVRNA levelsandCD4+lymphocytecountspredictboth response toantiretroviral therapyandtherapeuticfailure.VACooperativeStudyGrouponAIDS.AnnInternMed.1997Jun15;126(12):939-45.

[40] HoggR,YipB,ChanKJ,WoodE,CraibKJ,O’ShaughnessyMV,MontanerJS,etal.RatesofdiseaseprogressionbybaselineCD4cellcountandviralloadafterinitiatingtriple-drugtherapy.(0098-7484).

��

[41] GrabarS,LeMoingV,GoujardC,EggerM,LeportC,KazatchkineMD,etal.Responsetohighlyactiveantiretroviraltherapyat6monthsandlong-termdiseaseprogressioninHIV-1infection.JAcquirImmuneDeficSyndr.2005Jul1;39(3):284-92.

[42] BretonG,DuvalX,EstellatC,PoalettiX,BonnetD,MvondoMvondoD,etal.DeterminantsofimmunereconstitutioninflammatorysyndromeinHIVtype1-infectedpatientswithtuberculosisafterinitiationofantiretroviraltherapy.ClinInfectDis.2004Dec1;39(11):1709-12.

[43] Buckingham SJ, Haddow LJ, Shaw PJ, Miller RF. Immune reconstitution inflammatorysyndromeinHIV-infectedpatientswithmycobacterialinfectionsstartinghighlyactiveanti-retroviraltherapy.ClinRadiol.2004Jun;59(6):505-13.

[44] Goebel FD. Immune reconstitution inflammatory syndrome (IRIS)--another new diseaseentityfollowingtreatmentinitiationofHIVinfection.Infection.2005Feb;33(1):43-5.

[45] Lortholary O, Fontanet A, Memain N, Martin A, Sitbon K, Dromer F. Incidence and riskfactors of immune reconstitution inflammatory syndrome complicating HIV-associatedcryptococcosisinFrance.AIDS.2005Jul1;19(10):1043-9.

[46] ShelburneSA,VisnegarwalaF,DarcourtJ,GravissEA,GiordanoTP,WhiteAC,Jr.,etal.Incidenceandriskfactorsforimmunereconstitutioninflammatorysyndromeduringhighlyactiveantiretroviraltherapy.AIDS.2005Mar4;19(4):399-406.

[47] NishanianP,TaylorJM,MannaB,AzizN,GrosserS,GiorgiJV,DetelsR,etal.Acceleratedchanges(inflectionpoints) in levelsofserum immuneactivationmarkersandCD4+andCD8+ T cells prior to AIDS onset. (1077-9450). J Acquir Immune Defic Syndr. 1998 Jan7;279(1):35-40.

[48] MacDonellKb-ChmielJS,PoggenseeL,WuS,PhairJP.PredictingprogressiontoAIDS:combinedusefulnessofCD4lymphocytecountsandp24antigenemia.(0002-9343).HumRetroviral.1998Jan7;279(1):35-40.

[49] Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, et al.Plasmaviral loadandCD4+ lymphocytesasprognosticmarkersofHIV-1 infection.AnnInternMed.1997Jan15;126(12):946-54.

[50] PENTA.HIV-1viral loadandCD4cellcount inuntreatedchildrenwithverticallyacquiredasymptomaticormilddisease.PaediatricEuropeanNetworkforTreatmentofAIDS(PENTA).Jan1;18(2):162-70(0269-9370).

[51] VajpayeeM,KaushikS,SreenivasV,WigN,SethP.CDCstagingbasedonabsoluteCD4countandCD4percentageinanHIV-1-infectedIndianpopulation:treatmentimplications.ClinicalandExperimentalImmunology.2005;141(3):485-90.

[52] Vlahov D, Graham N, Hoover D, Flynn C, Bartlett JG, Margolick JB, Lyles CM, et al.PrognosticindicatorsforAIDSandinfectiousdiseasedeathinHIV-infectedinjectiondrugusers:plasmaviralloadandCD4+cellcount.Jama.1998Jan7;279(1):35-40.


[53] BundersM,Cortina-BorjaM,NewellML.Age-relatedstandardsfortotallymphocyte,CD4+andCD8+TcellcountsinchildrenborninEurope.PediatrInfectDisJ.2005Jul;24(7):595-600.

[54] CareyVJ,PahwaS,WeinbergA.ReliabilityofCD4quantitationinhumanimmunodeficiencyvirus-positivechildren:implicationsfordefinitionofimmunologicresponsetohighlyactiveantiretroviraltherapy.ClinDiagnLabImmunol.2005May;12(5):640-3.

[55] MofensonLM,HarrisDR,MoyeJ,BethelJ,KorelitzJ,ReadJS,etal.AlternativestoHIV-1RNAconcentrationandCD4counttopredictmortalityinHIV-1-infectedchildreninresource-poorsettings.Lancet.2003Nov15;362(9396):1625-7.

[56] Ochieng W, Ogoyi D, Mulaa FJ, Ogola S, Musoke R, Otsyula MG. Viral load, CD4+ T-lymphocyte counts and antibody titres in HIV-1 infected untreated children in Kenya;implicationforimmunodeficiencyandAIDSprogression.AfrHealthSci.2006Mar;6(1):3-13.

[57] ShahI.CorrelationofCD4count,CD4%andHIVviral loadwithclinicalmanifestationsofHIVininfectedIndianchildren.AnnTropPaediatr.2006;26(2):115-9.

[58] vanBenthemBHVP,CoutinhoRA,PrinsM,.EuropeanStudyontheNaturalHistoryofHIVInfectioninWomenandtheSwissHIVCohortStudy.AIDS.2002;16(6)(Apr12):919-24.

[59] Waecker NJ, Jr., Ascher DP, Robb ML, Moriarty R, Krober M, Rickman WJ, et al. Age-adjusted CD4+ lymphocyte parameters in healthy children at risk for infection with thehumanimmunodeficiencyvirus.TheMilitaryPediatricHIVConsortium.ClinInfectDis.1993Jul;17(1):123-5.

[60] 1993 revised classification system for HIV infection and expanded surveillance casedefinition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992 Dec18;41(RR-17):1-19.

[61] ChearskulS,ChotpitayasunondhT,SimondsRJ,WanpraparN,WaranawatN,PunpanichW, et al. Survival, disease manifestations, and early predictors of disease progressionamong children with perinatal human immunodeficiency virus infection in Thailand.Pediatrics.2002Aug;110(2Pt1):e25.

[62] JohnstonAM,ValentineME,OttingerJ,BaydoR,GryszowkaV,VavroC,WeinholdK,etal.Immunereconstitutioninhumanimmunodeficiencyvirus-infectedchildrenreceivinghighlyactive antiretroviral therapy: a cohort study. (0891-3668). Pediatr Infect Dis J. 2001Oct;20(10):941-6.

[63] GhaffariG,PassalacquaDJ,CaicedoJL,GoodenowMM,SleasmanJW.Two-yearclinicalandimmuneoutcomesinhumanimmunodeficiencyvirus-infectedchildrenwhoreconstituteCD4 T cells without control of viral replication after combination antiretroviral therapy.Pediatrics.2004Nov;114(5):e604-11.

��

[64] NewellML,PatelD,GoetghebuerT,ThorneC.CD4cellresponsetoantiretroviraltherapyinchildrenwithverticallyacquiredHIVinfection:isitassociatedwithageatinitiation?JInfectDis.2006Apr1;193(7):954-62.

[65] ResinoS,BellonJM,RamosJT,ResinoR,GurbindoMD,MelladoMJ,etal.Impactofhighlyactive antiretroviral therapy on CD4+ T cells and viral load of children with AIDS: apopulation-basedstudy.AIDSResHumRetroviruses.2004Sep;20(9):927-31.

[66] Nikolic-Djokic D, Essajee S, Rigaud M, Kaul A, Chandwani S, Hoover W, et al.ImmunoreconstitutioninchildrenreceivinghighlyactiveantiretroviraltherapydependsontheCD4cellpercentageatbaseline.JInfectDis.2002Feb1;185(3):290-8.

[67] Cohen Stuart JW, Slieker WA, Rijkers GT, Noest A, Boucher CA, Suur MH, et al. EarlyrecoveryofCD4+Tlymphocytesinchildrenonhighlyactiveantiretroviraltherapy.DutchstudygroupforchildrenwithHIVinfections.Aids.1998Nov12;12(16):2155-9.

[68] UppalSS,TewariSC,VermaS,DhotPS.ComparisonofCD4andCD8lymphocytecountsinHIV-negativepulmonaryTBpatientswiththoseinnormalblooddonorsandtheeffectofantitubercular treatment:hospital-basedflowcytometricstudy.CytometryBClinCytom.2004Sep;61(1):20-6.

[69] Jiang W, Kang L, Lu HZ, Pan X, Lin Q, Pan Q, et al. Normal values for CD4 and CD8lymphocyte subsets in healthy Chinese adults from Shanghai. Clin Diagn Lab Immunol.2004Jul;11(4):811-3.

[70] SomersetDA,ZhengY,KilbyMD,SansomDM,DraysonMT.Normalhumanpregnancyisassociatedwithanelevation in the immunesuppressiveCD25+CD4+ regulatoryT-cellsubset.Immunology.2004May;112(1):38-43.

[71] UppalSS,VermaS,DhotPS.NormalvaluesofCD4andCD8lymphocytesubsetsinhealthyindianadultsandtheeffectsofsex,age,ethnicity,andsmoking.CytometryBClinCytom.2003Mar;52(1):32-6.

[72] RamalingamS,KannangaiR,ZachariahA,MathaiD,AbrahamC.CD4countsofnormalandHIV-infectedsouthIndianadults:doweneedanewstagingsystem?NatlMedJIndia.2001Nov-Dec;14(6):335-9.

[73] KannangaiR,PrakashKJ,RamalingamS,AbrahamOC,MathewsKP,JesudasonMV,etal.PeripheralCD4+/CD8+T-lymphocytecountsestimatedbyanimmunocapturemethodinthenormalhealthysouthIndianadultsandHIVseropositiveindividuals.JClinVirol.2000Aug;17(2):101-8.

[74] FernandezS,RosenowAA,JamesIR,RobertsSG,NolanRC,FrenchMA,etal.RecoveryofCD4+TCellsinHIVpatientswithastablevirologicresponsetoantiretroviraltherapyisassociated with polymorphisms of interleukin-6 and central major histocompatibilitycomplexgenes.JAcquirImmuneDeficSyndr.2006Jan1;41(1):1-5.


[75] BrigidoL,RodriguesR,CassebJ,CustodioRM,FonsecaLA,SanchezM,etal.CD4+T-cellrecoveryandclinicaloutcomeinHIV-1-infectedpatientsexposedtomultipleantiretroviralregimens: partial control of viremia is associated with favorable outcome. AIDS PatientCareSTDS.2004Apr;18(4):189-98.

[76] BennettKK,DeGruttolaVG,MarschnerIC,HavlirDV,RichmanDD.BaselinepredictorsofCD4T-lymphocyterecoverywithcombinationantiretroviraltherapy.JAcquirImmuneDeficSyndr.2002Sep1;31(1):20-6.

[77] ViardJP,MocroftA,ChiesiA,KirkO,RogeB,PanosG,etal.InfluenceofageonCD4cellrecovery in human immunodeficiency virus-infected patients receiving highly activeantiretroviral therapy: evidence from the EuroSIDA study. J Infect Dis. 2001 Apr15;183(8):1290-4.

[78] FrancoJM,Leon-LealJA,LealM,Cano-RodriguezA,PinedaJA,MaciasJ,etal.CD4+andCD8+Tlymphocyteregenerationafteranti-retroviraltherapyinHIV-1-infectedchildrenandadultpatients.ClinExpImmunol.2000Mar;119(3):493-8.

[79] MellorsJM,A.Giorgi,J.V.Margolick,J.B.Tassoni,C.J.Gupta,P.Kingsley,L.A.Todd,J.A. Saah, A. J. Detels, R. Phair, J. P. Rinaldo, C. R., Jr. Plasma viral load and CD4+lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997 Jun15;126(12):946-54.

[80] Lafeuillade A, Tamalet C, Pellegrino P, de Micco P, Vignoli C, Quilichini R,. Correlationbetween surrogate markers, viral load, and disease progression in HIV-1 infection.(0894-9255).

[81] MellorsJW,RinaldoCR,Jr.,GuptaP,WhiteRM,ToddJA,KingsleyLA.PrognosisinHIV-1infectionpredictedbythequantityofvirusinplasma.Science.1996May24;272(5265):1167-70.

[82] TemmermanMNN,BwayoJ,ChombaEN,Ndinya-AcholaJ,PiotP.HIV-1andimmunologicalchanges during pregnancy: a comparison between HIV-1-seropositive and HIV-1-seronegativewomeninNairobi,Kenya.AIDS.1995Sep;9(9):1057-60.

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ISBN 978 92 4 159562 9

For more information, contact:

World Health Organization Department of HIV/AIDS

20, avenue Appia 1211 Geneva 27 Switzerland

E-mail: [email protected]

www.who.int/hiv

Photograph: Gideon Mendel/The International HIV/AIDS Alliance/Corbis

HIV/AIDS Programme · HIV human immunodeficiency virus PMTCT prevention of mother to child transmission ( of HIV) RNA ribonucleic acid WHO World Health Organization EIA Enzyme Immunoassay

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