Anti Retroviral Therapy guidelines

7/30/2019 Anti Retroviral Therapy guidelines

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ANTIRETROVIRAL THERAPY

OF HIV INFECTION IN INFANTS

AND CHILDREN:

TOWARDS UNIVERSAL ACCESS

Recommendations

for a public health approach

Strengthening health services to fght HIV/AIDSHIV/AIDS Programme


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World Health Organization 2006

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ANTIRETROVIRAL THERAPYOF HIV INFECTION IN INFANTS

AND CHILDREN:

TOWARDS UNIVERSAL ACCESS

Recommendationsfor a public health approach

2006


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ii


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iii

Abbreviations. iv

I. Introduction. 1II. Objectives.o.the.Guidelines. 2

III. Development.o.the.Guidelines. 3

IV. Establishing.Diagnosis.o.HIV.Inection. 5

V. When.to.Start.Antiretroviral.Therapy.in.Inants.and.Children.11

VI. What.to.Start..Recommended.First-Line.ARV.Regimens.in.Inants.and.Children. 18

VII. Considerations.or.ART.in.Inants.Previously.Exposed.to.ARV.Drugs. 26

VIII. Antiretroviral.Drug.Toxicity. 28

IX. Substituting.Within.a.First-Line.ARV.Regimen.in.Inants.and.Children.because.o.Drug.Toxicity. 31

X. Switching.an.ARV.Regimen.in.Inants.and.Children:.Treatment.Failure. 33

XI. Choice.o.ARV.Regimens.in.the.Event.o.Treatment.Failure.o.First-Line.Regimens.in..Inants.and.Chi ldren..Second-Line.Regimens. 39

XII. Considerations.or.Inants.and.Children.Coinected.With.Tuberculosis.and.HIV. 43

XIII. Considerations.or.Nutrition.in.HIV-Inected.Inants.and.Children. 50

XIV. Considerations.or.ART.in.Adolescents. 53

XV. Clinical.and.Laboratory.Monitoring. 55

XVI. Adherence.to.ART. 59

XVII. Strategies.in.the.Event.o.Failure.o.Second-Line.Regimens. 62

XVIII.Drug.Resistance. 64

Annex.A:. Members.o.the.technical.reerence.group.on.paediatric.HIV.care.and.treatment. 66

Annex.B:. Par t.A:.WHO.cl inical.staging.o.HIV.or.inants.and.children..with.established.hiv.inection. 68

Annex.B:. Par t.B:.Presumptive.and.denitive.criteria.or.recognizing.HIV.related.clinical..events.in.inants.and.children.with.established.HIV.inection. 70

Annex.C:. WHO.classication.o.HIV-associated.immunodeciency.in.inants.and.children. 77

Annex.D:. 12-Month.mortality.risk.at.selected.thresholds.or.%CD4+,..absolute.CD4.count.and.total.lymphocyte.count.by.age. 78

Annex.E:. Prescribing.inormation.and.weight.based.dosing.o.available.ARV.ormulations. .or.inants.and.children. 79

Annex.F:. Serious.acute.and.chronic.toxicities.caused.by.ARV.drugs,.possibly.requiring..therapy.modication:.clinical.presentation,.laboratory.abnormalities.and.implications.or.ART.management.117

Annex.G:. Severity.grading.o.selected.clinical.and.laboratory.toxicities..most.commonly.seen.with.recommended.ARV.drugs.or.children.121

Annex.H:. Sexual.maturi ty.rating.(Tanner.staging).in.adolescents. 127

Annex.I:. Recommended.tiered.laborator y.capabilit ies.or.ART.monitoring.in..resource-limited.settings 129

Reerences 130

CONTENTS


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ivAntiretrovirAl therApy of hiv infection in infAnts And children:

towArds universAl Access

AbbREVIATIONS

3TC. lamivudine

Ab. antibodyABC. abacavirACTG. AIDS.clinical.trials.groupAFB. acid-ast.bacilliAIDS. acquired.immunodeciency.

syndromeALT. alanine.aminotranserase.a.m.. ante.meridiem.(denotes.morning)

ART. antiretroviral.therapyARV. antiretroviral.(drug)AST . aspartate.aminotranseraseAUC. area.under.curveAZ T. zidovudine.(also.known.as.ZDV)BAL. bronchoalveolar.lavageb.d.. twice.dailyBSA . body.surace.areaCD4+. T-lymphocyte.bearing.CD4.receptorCHAP. Children.with.HIV.Antibody.

Prophylaxis.(clinical.trial)CMV . cytomegalovirusCNS. central.nervous.systemCPK. creatinine.phosphokinaseCPT. co-trimoxazole.preventive.therapyCRAG. cryptococcal.antigenCSF. cerebrospinal.fuid

CT. computerized.tomographyCTX. co-trimoxazoleCXR . chest.X-rayd4T. stavudineDART. Development.o.Antiretroviral.

Therapy.(in.Arica)DBS. dried.blood.spot.ddI. didanosineDNA. deoxyribonucleic.acidDOT. directly.observed.therapyEFV. eavirenzEIA. enzyme.immunoassayEMEA. European.Medicines.Agency.

ELISA. enzyme-linked.immunosorbent.assay.

FBC. ull.blood.countFDA. Food.and.Drug.AdministrationFDC. xed-dose.combinationFTC. emtricitabineGI. gastrointestinalHDL. high-density.lipoproteinHgb. haemoglobinhgc . hard.gel.capsuleHIV. human.immunodeciency.virusHIVDR . HIV.drug.resistanceHIVNET. HIV.Network.or.Prevention.TrialsHIVResNet. Global.HIV.Drug.Resistance.

NetworkHPPMCS. HIV.Paediatric.Prognostic.Markers.

Collaborative.StudyHSV . herpes.simplex.virus

ICD . immune.complex.dissociated

IDV . indinavirIMCI. integrated.management.o.childhood.illness

INH. isoniazidIRIS. immune.reconstitution.

infammatory.syndromeLDH. lactic.dehydrogenase.LDS. lipodystrophy.LGE . lineal.gingival.erythema.LIP . lymphocytic.interstitial.pneumoniaLPV. lopinavirLTB. laryngotracheal.bronchitisMRI . magnetic.resonance.imagingMTCT. mother-to-child.transmission.(o.HIV)NFV. nelnavir.NNRTI. non-nucleoside.reverse.

transcriptase.inhibitorNPA. nasopharyngeal.aspirateNRTI. nucleoside.reverse.transcriptase.

inhibitorNVP. nevirapineOHL. oral.hairy.leukoplakiaPACTG. Paediatric.AIDS.Clinical.Trials.GroupPCP. Pneumocystis.pneumoniaPCR. polymerase.chain.reaction

PENTA. Paediatric.European.Network.or.Treatment.o.AIDS.PGL. persistent.generalized.

lymphadenopathyPI. protease.inhibitorp.m.. post.meridiem.(denotes.aternoon)PML. progressive.multiocal.

leukoencephalopathyPMTCT. prevention.o.mother-to-child.

transmission.(o.HIV)/r. low-dose.ritonavirRDA . recommended.daily.allowanceRNA. ribonucleic.acid.

RT. reverse.transcriptase.RTI. reverse.transcriptase.inhibitorRTV. ritonavirRTV-PI. ritonavir-boosted.protease.inhibitorSD. standard.deviation.SJS. Stevens-Johnson.syndromeSQV. saquinavirSTI . structured.treatment.interruptionTB. tuberculosisTDF. tenoovir.disoproxil.umarateTEN . toxic.epidermal.necrolysisTLC . total.lymphocyte.countTRG . Technical.Reerence.GroupULN. upper.limit.o.normalUp24 Ag. ultrasensitive.p24.antigenURTI. upper.respiratory.tract.inectionWBC. white.blood.cell.countWHO. World.Health.Organization


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The.most.ecient.and.cost-eective.way.to.tackle.paediatric.HIV.globally.is.to.reduce.mother-

to-child.transmission.(MTCT).However,.every.day.there.are.nearly.1500.new.inections.in.children.under.15.years.o.age,.more.than.90%.o.them.occurring.in.the.developing.world.and.most.being.associated.with.MTCT.(1).HIV-inected.inants.requently.present.with.clinical.symptoms.in.the.rst.year.o.lie,.and.by.one.year.o.age.an.estimated.one-third.o.inected.inants.will.have.died,.and. about. hal. by.2. years.o. age. (2,.3).There. is.thus.a. critical. need. to.provide. antiretroviral.therapy.(ART). or.inants.and.children.who.become.inected.despite.the.eorts.being.made.to.prevent.such.inections.

In.countries.where.it.has.been.successully.introduced,.ART.has.substantially.changed.the.ace.o.HIV.inection.HIV-inected.inants.and.children.now.survive. to.adolescence.and.adulthood.

The.challenges.o.providing.HIV.care.have.thereore.evolved.to.become.those.o.chronic.as.well.as. acute. care. In. resource-limited. settings,. many. o. which. are. countries. hardest. hit. by. the.epidemic,.unprecedented.eorts.made.since.the.introduction.o.the.3.by.5.targets.and.global.commitments.to.rapidly.scale.up.access.to.ART.have.led.to.remarkable.progress.However,.this.urgency.and.intensity.o.eort.have.met.with.less.success.in.extending.the.provision.o.ART.to.HIV-inected. children. Signicant. obstacles. to. scaling. up. paediatric. care. remain,. including.limited.screening.or.HIV,.a.lack.o.aordable.simple.diagnostic.testing.technologies,.a.lack.o.human.capacity,.insucient.advocacy.and.understanding.that.ART.is.ecacious.in.children,.limited.experience.with.simplied.standardized.treatment.guidelines,.and.a.lack.o.aordable.

practicable.paediatric.antiretroviral.(ARV).ormulations.Consequently,.ar.too.ew.children.have.been. started. on. ART. in. resource-limited. settings. Moreover,. the. need. to.treat. an.increasing.number.o.HIV-inected.children.highlights.the.primary.importance.o.preventing.the.transmission.o.the.virus.rom.mother.to.child.in.the.rst.place.

WHO.guidelines.or.the.use.o.ART.in.children.were.considered.within.the.guidelines.or.adults.published.in.2004.(4).Revised,.stand-alone.comprehensive.guidelines.based.on.a.public.health.approach.have.been.developed.in.order.to.support.and.acilitate.the.management.and.scale-up.o.ART.in.inants.and.children

The.present.guidelines.are.part.o.WHOs.commitment.to.achieve.universal.access.to.ART.by.2010.

Related. publications. include. the. revised. treatment. guidelines. or. adults. (ie. the. 2006. revision),.revised.guidelines.on.ARV.drugs.or.treating.pregnant.women.and.preventing.HIV.inection.in.inants,.guidelines.on.the.use.o.co-trimoxazole.preventive.therapy.(CPT),(i).and.revised.WHO.clinical.staging.or.adults.and.children.(5).

(i). These.three.documents.are.available.at.http://wwwwhoint/hiv/pub/guidelines/en.

1. INTRODUCTION


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2AntiretrovirAl therApy of hiv infection in infAnts And children:


These.stand-alone.treatment.guidelines.serve.as.a.ramework.or.selecting.the.most.potent.and.

easible.rst-line.and.second-line.ARV.regimens.as.components.o.expanded.national.responses.or.the.care.o.HIV-inected.inants.and.children.Recommendations.are.provided.on:.

. diagnosing.HIV.inection.in.inants.and.children;.

. when. to.start. ART,.including. situations. where.severe.HIV. disease. in.children. less.than.18.months.o.age.has.been.presumptively.diagnosed;.

. clinical.and.laboratory.monitoring.o.ART;.

. substitution.o.ARVs.or.toxicities.

The.guidelines.consider.ART.in.dierent.situations,.eg.where.inants.and.children.are.coinected.with.HIV.and.TB.or.have.been.exposed.to.ARVs.either.or.the.prevention.o.MTCT.(PMTCT).or.because.o.breasteeding.rom.an.HIV-inected.mother.on.ART.They.address.the.importance.o.nutrition.in.the.HIV-inected.child.and.o.severe.malnutrition.in.relation.to.the.provision.o.ART.Adherence.to.therapy.and.viral.resistance.to.ARVs.are.both.discussed.with.reerence.to.inants.and.children.A.section.on.ART.in.adolescents.briefy.outlines.key.issues.related.to.treatment.in.this.age.group.

WHO strongly recommends that Paediatic ormulations including fxed dose combinations

(FDC) o ARVs be made available by the Pharmaceutical Industry. Consultation betweenpar tners including the Pharmaceutical Industry and medecines regulator y authorities will

be pursued in a separate process. This guideline does not thereore cover the specifc

needs or ARV drug development.

WHO.recognizes.the.need.to.strengthen.health.systems,.including.human.resources.capacity.and.monitoring.capabilities,.with.a.view.to.maximizing.the.quality.and.long-term.benets.o.therapy.Improved.access.to.HIV.diagnostic.testing.as.well.as.to.immunological.assays.or.measuring.%.CD4+.or.absolute.CD4.cell.counts.or.inants.and.young.children.is.important.or.

assisting. in. decision-making. on. initiation. and. optimizing. ART. The. inability. to. diagnose. HIV.inection.early.in.children,.severely.limits.access.to.ART.and/or.its.timely.initiation.

This. publication. is. primarily. intended. or. use. by. treatment. advisory. boards,. national. AIDS.programme. managers. and. other. senior. policy-makers. who. are. involved. in. the. planning. o.national.and.international.HIV.care.strategies.or.children.in.resource-limited.countries.

The.major.limitation.in.developing.these.guidelines.is.the.lack.o.appropriate.ARV.ormulations.or.use.in.children,.and.in.certain.situations.the.only.available.option.may.be.to.use.ARV.products.intented.or.adult.use

II. ObjECTIVES OF THE GUIDELINES


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3

III. DEVELOPmENT OF THE GUIDELINES

Since.the.original.guidance.on.ART.or.inants.and.children.became.available.in.2004.there.have.

been.advances.in.the.diagnosis.and.treatment.o.HIV,.and.data.have.emerged.on.ecacy,.resistance,.drug-drug.interactions.and.the.long-term.toxicities.o.ART.based.on.use.in.resource-limited.settings.At.a.consultation.o.the.Technical.Reerence.Group.on.Paediatric.HIV.Care.and.Treatment. (TRG). in.Geneva. on. 2021.June. 2005,.experts.reviewed. and.assessed. scientic.evidence.and.experiences.in.the.scaling.up.o.paediatric.ART.and.HIV. care.This.consultation.provided.the.basis.or.the.present.recommendations.In.giving.their.advice.the.experts.considered.the.ollowing.overarching.principles

. ART. programmes. should. be. scaled. up. with. a. view. to. universal. access,. ie. all. persons,.including.inants.and.children,.requiring.treatment.as.indicated.by.medical.criteria.should.

have.access. to.it,.and.the. treatment. o.inants. and. children.in. need. o.ART. according.to.national.and.international.guidelines.should.begin.as.soon.as.is.practicable

. To. support. implementation,. ARV. regimens. should. be. standardized. and. simplied. The.recommendations.in.these.guidelines.are.harmonized.with.the.WHO.guidelines.on.treatment.in.adults,. ARVs. or. treating.pregnant.women. and. preventing. MTCT. o.HIV. to.inants,.and.post-exposure.prophylaxis.

. ART.recommendations.should.be.based.on.the.best.available.scientic.evidence,.avoiding.the.use.o.substandard.protocols.that.compromise.the.outcomes.o.individual.patients.and.

creating.a.potential.or.the.emergence.o.drug-resistant.virus,.and.on.regimens.that.both.oer.a.durable.response.and.preserve.uture.treatment.options

. The. recommendations. should. be. based. on. evidence. rom. randomized. controlled. trials,.high-quality. scientic. studies. or. non-treatment. related. options,. or. observational. cohort.data,.or,.i.insucient.evidence.is.available,.on.expert.opinion,.and.they.should.be.identied.as.such.The.strength.o.the.recommendations.has.been.indicated.as.a.guide.to.the.degree.to.which.they.should.be.considered.by.country.programmes.(Table.1).

. Cost-eectiveness.was.not.explicitly.considered.as.part.o.these.recommendations,.although.the.realities.with.respect.to.the.availability.o.human.resources,.health.system.inrastructures.

and.socioeconomic.contexts.were.taken.into.account

. Revisions.to.existing.recommendations.should.not.disrupt.the.scale-up.eorts.already.under.way.in.countries.Adaptations.in.accordance.with.prevailing.local.situations.may.be.necessary.in.order.to.acilitate.implementation

Following.the.production.o.drat.guidelines.by.the.designated.writing.committee,.the.document.was.sent.to.institutional.and.organizational.partners.worldwide.and.made.available.on.the.WHO.website.or.public.consultation.during.the.period.312.November.2005.At.a.consultation.o.the.writing. committee. in. Geneva. on. 1718. November. 2005,. all. comments. were. validated. and.

addressed,.as.appropriate,.in.the.nal.document,.which.has.been.reviewed.again.by.the.TRG.(a.list.o.TRG.members.is.provided.in.Annex.A).


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Table . Grading o recommendations and levels o evidence

Strength o recommendation Level o evidence to guiderecommendation

A. Recommended..should.be.ollowed

B. Consider..applicable.in.most.situations

C. Optional

I. At.least.one.randomized.controlled.trial.with.clinical,.laboratory.or.programmatic.endpoints

II. .At.least.one.high.quality.study.or.several.adequate.studies.with.clinical,.

laboratory.or.programmatic.endpoints.III. Observational.cohort.data,.one.or.more.

case.controlled.or.analytic.studies.adequately.conducted.

IV. Expert.opinion.based.on.evaluation.o.other.evidence

Source: Adapted.rom.reerences.(6).and.(7 ),.and:WHO.Evidence.Network,.http://wwweurowhoint/HEN/Syntheses/hepatitisC/20050408_5Evidence-based.medicine,.http:.//wwwebm-guidelines.com/ebmg/itkkati


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This.section.summarizes.WHO.recommendations.or.establishing.the.presence.o.HIV.inection (i ).

in.order.to.ensure.that.inants.and.children.can.access.HIV.care.and.treatment.and.to.aid.clinical.management.The.denitive.diagnosis.o.HIV.inection.in.children.at.any.age.requires.diagnostic.testing. that. conrms. the. presence. o. the. human. immunodeciency. virus. Antibody. testing.identies.HIV.antibody.However,.maternal.HIV.antibody.is.transerred.passively.during.pregnancy.and.may.rarely.persist.beyond.the.rst.12.months.o.lie.in.children.born.to.HIV-inected.mothers.[8].making.the.interpretation.o.positive.HIV.antibody.test.results.dicult.In.order.to.diagnose.HIV.inection.denitively.in.children.aged.under.18.months,.assays.that.detect.the.virus.or.its.components.(ie.virological.tests).are.thereore.required.Virological.tests.that.can.be.used.in.children.include:

. assays.to.detect.HIV.DNA.[9];

. assays.to.detect.HIV.RNA.[10-14];

. assays.to.detect.p24.antigen.[15-17]

The.technology.or.virological.tests.is.oten.considered.too.costly.and.complex.or.roll-out.in.low-resource.settings.Real-time.PCR.detects.HIV-RNA.and.HIV-DNA.and.several.automated.platorms.are.commercially.available.It.has.become.cheaper.and.easier.to.standardize.than.with.previous.methods.or.PCR,.providing.several.advantages.in.the.early.diagnosis.o.HIV.inection. in. children. and. the. monitoring. o. the. eectiveness. o. ART. [13]. Ultrasensitive. p24.

(Up24Ag).assays.are.also.promising.alternatives.or.use.in.resource-constrained.settings.[18].The. evaluation. o. such. technologies. merits. urther. research. and. urgent. standardization.Regardless.o.the.testing.technology.that.will.be.introduced.on.a.wider.scale,.the.reliability.o.laboratories.should.be.continuously.ensured.with.standard.quality.assessments

Blood. may. be. dicult. to. collect. rom. young. inants. and. must. be. sent. immediately. to. the.laboratory.More.recently,.the.use.o.dried.blood.spots.(DBSs).or.both.HIV-DNA.or.HIV-RNA.testing. and. Up24Ag. assay. has. proved. robust. and. reliable. [19-26]. DBSs. do. not. require.venepuncture.but.can.be.obtained.by.using.blood.rom.a.nger-stick.or.heel-stick.They.carry.a.smaller.biohazard.risk.than.liquid.samples,.are.stable.at.room.temperature.or.prolonged.periods.

and. are. easier. to. ship,. thus. acilitating. centralized. laboratory. testing. [19]. The. use. o. DBSs.should.be.more.widely.implemented.in.order.to.improve.access.to.virological.testing.in.a.range.o.resource-limited.settings.

National.programmes.in.charge.o.PMTCT.and.the.provision.o.ART.should.strive.to.ensure.that.diagnostic.protocols.are.in.place.or.systematic.testing.o.HIV-exposed.inants.and.children,.and.o.symptomatic.children.where.HIV.is.suspected,.including.the.availability.o.virological.tests.that.allow.early.diagnosis.o.HIV.inection.in.young.children.The.identication.and.ollow-up.o.inants.born.to.HIV-inected.women.are.a.necessary.rst.step.in.inant.diagnosis.It.needs.to.be.emphasized.that.children.under.18.months.o.age.who.are.known.or.suspected.to.have.been.exposed.to.HIV.

should.be.closely.monitored.and.should.benet.early.in.lie.rom.interventions.such.as.CPT,.even.where.virological.testing.is.not.available.or.the.denitive.diagnosis.o.HIV.inection.

i. Technical.recommendations.on.diagnosis.and.case.denitions.or.HIV.inection.in.inants.and.children.are.published.separately.and.are.being.updated.in.2006.

IV. ESTAbLISHING DIAGNOSIS OF HIV INFECTION


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AntiretrovirAl therApy of hiv infection in infAnts And children:


In.children.aged.18.months.or.more,.HIV.antibody.tests,.including.rapid.antibody.tests.(either.

rapid.HIV.tests.or.laboratory.based.HIV.antibody.enzyme.immunoassays.[EIAs].or.a.combination.o.both),.can.be.reliably.used.to.diagnose.HIV.inection.denitively.in.the.same.manner.as.they.are.used.in.adults(i )

While.HIV.antibody.testing.cannot.be.used.to.diagnose.HIV.inection.denitively.in.inants.under.18.months.o.age,.it.can.be.useul.or.identiying.potentially.uninected.inants.as.early.as.9.to.12.months.o.age,.as.most.uninected.HIV-exposed.inants.lose.maternal.HIV.antibody.by.the.age.o.12.months.(see.also.section.on.breasteeding.inants)..

Additional. investment. by. governments. to. improve. access. to. earlier. HIV. diagnosis. or. inants.

could.lead.to.a.notable.increase.in.the.eciency.o.PMTCT.programmes.in.identiying.HIV-inected. children,. acilitating. medical. management,. reducing. morbidity. and. mortality. and.improving.the.quality.o.lie.In.addition,.early.diagnosis.oers.other.benets.that.extend.beyond.economic.savings.[27]

Children.may.or.may.not.have.a.living.parent.or.identied.legal.guardian.and.issues.o.consent,.competency.to.consent,.disclosure,.condentiality.and.counselling.have.to.be.considered.National.policies.need.to.be.clear.in.their.recommendations.on.how.to.provide.HIV.testing.services.to.inants.and.children,.and.programmes.should.ensure.tools.and.resources.provide.clear.specic.guidance.on.inormed.consent,.counselling,.inorming.and.disclosure.or.HIV.testing.in.children(ii).

I.HIV.inection.is.diagnosed.in.a.young.child.or.inant.the.mother.hersel.is.usually.HIV-inected.and.partners.and.other.siblings.may. also.be.inected. Appropriate.counselling.and. support. should.thereore.be.provided.to.amilies.when.testing.or.HIV.in.children.

Children aged under 8 months

Denitive.laboratory.diagnosis.o.HIV.inection.in.children.aged.under.18.months.can.only.be.made.by.conducting.virological.testing.For.the.purposes.o.clinical.management.including.the.initiation.o.ART.where.access.to.these.virological.tests.is.limited,.WHO.advises.that.the.rst.virological.testing.should.be.conducted.at.or.around.6.weeks.ollowing.birth.[28-30].Although.

earlier.virological.testing,.during.the.rst.48.hours.o.lie.o.an.HIV-exposed.inant,.can.identiy.inants.inected.in.utero,.those.inants.inected.during.late.pregnancy.and.intrapartum.will.have.negative.virological.tests.at.that.time.By.the.age.o.4.weeks,.virological.testing.approaches.98%.sensitivity. [30]. It. is. considered. more. programmatically. ecient. to. perorm. initial. virological.testing.rom.the.age.o.6.weeks.Positive.virological.testing.at.any.age,.however,.is.considered.indicative.o.HIV. inection.or.purposes.o.clinical.management.Preerably,.a. repeat.test.on.a.separate. specimen. should. be. peromed. to. conrm. an. initial. positive. test. It. is. recognized,.however,.that.in.severely.resource-constrained.settings,.repeat.virological.testing.on.either.the.same.specimen.or.a.separate.one.to.conrm.diagnosis.may.not.be.easible.or.aordable.

(i). The. precise. algorithms.or. combination.o. tests. required.to. diagnose.HIV. inection.or.diagnostic. and. surveillance.purposes.are.urther.explained.in.reerence.25

(ii). The.WHO.online. toolkit.on.HIV. testing.and.counselling.includes.a.section.o.resources.on.HIV.testing.and.counselling.in.children.and.is.available.at:.http://whoarvkitnet/tc/en/indexjsp


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In.these.situations.the.reliability.o.the.laboratory.(determined.by.standard.quality.assessment).

is.undamental.to.ensure.reliable.test.results.In.children.diagnosed.with.HIV.inection.on.the.basis.o.one.positive.virological.test,.HIV.antibody.testing.should.preerably.be.perormed.ater.18.months.o.age.in.order.to.conrm.HIV.inection.(Fig.1).

By.the.age.o.12.months.most.uninected.HIV-exposed.children.have.lost.maternal.antibody,.and.testing.HIV.antibody-positive.at.this.age.can.be.considered.indicative.o.HIV.inection.(ie.945%.seroreversion.at.the.age.o.12.months).[31-33].This.should.be.conrmed.by.repeat.antibody.testing.ater.the.age.o.18.months.

Diagnosing HIV inection in breasteeding inants

I.an.inant.is.breasteeding.he.or.she.remains.at.risk.o.acquiring.HIV.inection.throughout.the.breasteeding.period.It.is.not.necessary.to.stop.breasteeding.prior.to.perorming.diagnostic.HIV.virological.testing,.but.interpreting.negative.results.is.dicult.Positive.results.should.be.considered.to.refect.HIV.inection.and.usual.conmatory.algorithms.ollowed.On.the.basis.o.expert.opinion.WHO.advises.that.the.window.period.required.beore.negative.virological.test.results.can.be.assumed.to.reliably.indicate.HIV.inection.status.ater.the.complete.cessation.o.breasteeding.is.six.weeks.For.children.who.have.continued.to.breasteed.into.the.rst.year.o.lie.the.same.six.week.window.period.is.suggested.or.serological.HIV.antibody.testing.beore.negative.test.results.reliably.indicate.HIV.inection.status.

HIV-exposed symptomatic inants and childrenWhere.virological.testing.is.not.routinely.available,.any.child.under.9-12.months.o.age.known.to.be.HIV-exposed.and.developing.signs.and.symptoms.o.HIV.inection.should.be.reerred.or.virological.testing.Positive.virological.results.in.a.symptomatic.inant.or.child.indicate.HIV.inection.

Diagnosing HIV inection where mother or inant has received ARV drugs or PMTCT

When.HIV.DNA.assays.are.used.or.diagnosis,.the.use.o.ARV.drugs.in.the.mother.or.inant.or.PMTCT.should.not.aect.the.test.result.HIV.DNA.remains.detectable.in.the.peripheral.blood.mononuclear.cells.o.HIV-inected.children.who.have.received.ART.and.have.undetectable.viral.replication.as.measured.by.HIV.RNA.assays,.and.so.HIV.DNA.testing.can.be.conducted.in.inants.who.have.received.ARV.or.MTCT.prevention.There.are.theoretical.concerns.about.the.sensitivity.o.HIV.RNA.or.Up24Ag.assays.However.experts.based.on.currently.available.data.recommend.that.the.RNA.or.Up24Ag.can.be.used.at.any.time.rom.6.weeks.o.age.[12]

Diagnosing inection when the mother is on ART

It.is.not.known.whether.maternal.ART.during.breasteeding.aects.HIV.RNA.or.Up24Ag.detection.in.inants.in.the.light.o.the.relatively.high.ART.levels.ound.in.the.inants.o.breasteeding.mothers.[34],. DNA. detection. is. unaected. by. maternal. ART. Experts. recommend. that. all. the. above.methods.o.virological.testing.can.be.used.rom.6.weeks.o.age.even.i.the.mother.is.breasteeding.

and.on.ART.


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Children aged 8 months and more

Denitive.HIV.diagnosis.in.children.aged.18.months.and.more.(with.known.or.unknown.HIV.exposure).can.be.made.with.antibody.tests,.including.rapid.antibody.tests.ollowing.standard.testing.algorithms.used.or.adults.(Fig.1).The.conrmation.o.a.positive.antibody.test.result.should.ollow.standard.national.testing.algorithms,.and.at.a.minimum.should.involve.duplicate.testing.by.means.o.a.dierent.HIV.antibody.test.[35,.36].The.use.o.rapid.antibody.tests.or.diagnosis.has.the.advantage.that.the.results.become.available.at.the.time.o.the.clinic.visit

Presumptive clinical diagnosis o HIV inection

No.single.clinical.diagnostic.algorithm.has.proved.highly.sensitive.or.specic.or.the.diagnosis.o.HIV.inection.Clinical.algorithms.are.rarely.more.than.70%.sensitive.or.the.accurate.diagnosis.o.inection.[37].and.they.vary.considerably.with.age,.and.in.particular.they.are.less.reliable.in.children.aged.under.12.months.[38].HIV.antibody.testing,.especially.rapid.testing,.and.increased.access.to.early.virological.testing.must.be.made.available.to.help.clinicians.implement.improved.diagnostic.algorithms.However,.there.are.situations.where.the.use.o.a.clinical.algorithm.may.be.required.to.initiate.appropriate.lie-saving.treatment.o.a.seriously.ill.child.under.the.age.o.18.months.Currently,.insucient.data.are.available.to.make.rm.recommendations.on.the.use.o.clinical.algorithms.combined.with.the.measurement.o.CD4.or.other.parameters.or.establishing.

HIV.inection.It.should.be.emphasized.that.WHO.clinical.staging.o.HIV.disease.can.only.be.employed.where.HIV.inection.has.been.established

Children aged under 8 months

For.inants.and.children.aged.under.18.months.where.access.to.virological.testing.is.not.yet.available.but.where.there.are.symptoms.suggestive.o.HIV.inection,.accompanied.by.positive.HIV.antibody.testing,.a.presumptive.clinical.diagnosis.o.severe.HIV.inection.may.be.necessary.in.order.to.permit.decision-making.on.the.need.or.the.initiation.o.potentially.lie-saving.ART.(see.Section.V).

WHO.encourages.researchers.and.national.programmes.to.validate.approaches.to.presumptive.

clinical.diagnosis.in.children.under.18.months.o.age,.including.studies.to.determine.i.%.CD4.or.CD4/CD8.ratio.combined.with.clinical.signs.and.symptoms.improves.the.early.diagnosis.o.HIV.inection. WHO. urges. national. programmes. to. increase. access. to. diagnostic. testing. or. HIV.inection. or. all. children. born. to. HIV-inected. women. The. development. o. tests. applicable. to.resource-limited.settings.so.as.to.allow.early.diagnosis.o.HIV.inection.in.inants.is.critical.to.the.implementation.o.recommendations.or.the.initiation.o.appropriate.care,.including.ART,.in.children.aged.under.18.months.

Children aged 8 months and more

For. children. aged. 18. months. and. older. with. signs. and. symptoms. suggestive. o. HIV,. WHO.strongly.recommends.the.use.o.antibody.testing.ollowing.national.protocols.in.order.to.diagnose.HIV.inection.(Table.2.&.Fig.1).Presumptive.clinical.diagnosis.o.severe.HIV.disease.is.thereore.not.indicated.because.standard.HIV.antibody.testing.is.diagnostic.o.HIV.inection.in.this.age.group. Some. clinical. conditions. are. very. unusual. without. HIV. inection. (ie. Pneumocystis.


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pneumonia,.oesophageal.candidiasis,.lymphoid.interstitial.pneumonitis,.Kaposis.sarcoma.and.

cryptococcal.meningitis),.and.the.diagnosis.o.these.conditions.thus.suggests.HIV.inection.and.indicates.the.need.to.perorm.HIV.antibody.testing.

Table.2.summarizes.the.recommended.methodologies.or.establishing.the.presence.o.HIV(i )

Table 2. Summary o recommendations on methods or establishing the

presence o HIV inection in inants and children

Method odiagnosis

Recommendations or use Strength orecommendation/

level o evidenceVirologicalmethods

To.diagnose.inection.in.inants.and.children.aged.under.18.months;.initial.testing.is.recommended.rom.6.weeks.o.age

HIV.DNA.[A(I)]

HIV.RNA.[A(I)]

U.p24.ag.[CII]

HIVantibodytesting

To.diagnose.HIV.inection.in.mother.or.identiy.HIV.exposure.o.inant.

A(I)

To.diagnose.HIV.inection.in.children.aged.18.

months.or.more.

A(I)

To.identiy.HIV-antibody.positive.children.aged.under.18.months.and.support.the.presumptive.clinical.diagnosis.o.severe.HIV.disease.(section.V)

A(IV).a

To.exclude.HIV.inection.where.HIV.antibody.negative.in.children.aged.under.18.months.who.are.HIV.exposed.and.never.breasted.

.A(I)

To.exclude.HIV.inection.where.HIV.antibody.negative.in.children.aged.under.18.months.who.are.HIV.exposed.and.discontinued.breasteeding.or.more.than.6.weeks.

A.(IV )

a. Children.aged.under.18.months.who.have.positive.HIV.antibody.tests.include.those.who.are.truly.HIV-inected.and.those.who.have.persisting.maternal.antibody.but.are.uninected.By.the.age.o.12.months.most.uninected.children.have.lost.maternal.antibody.and.positive.antibody.testing.at.this.time.usually.indicates.HIV.inection,.although.conrmatory.testing.at.18.months.is.recommended.

(i). WHO. Technical.and. operational. recommendations. are.available. at:. http://dataunaidsorg/Publications/IRC-pub02/JC602-HIVSurvGuidel_enpd.&.http://wwwwhoint/diagnostics_laboratory/publications/en/HIV_Report15pd.


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Figure . Establishing presence of HIV infection in HIV exposed children aged under

8 months in resource-limited settings to facilitate ART and HIV care

a. The.risk.o.HIV.transmission.remains.i.breasteeding.continues.beyond.18.months.o.age.b. Inants.over.9.months.o.age.can.be.tested.initially.with.HIV.antibody.test,.as.those.who.are.HIV.Ab.negative.are.not.usually.HIV.

inected,.although.still.at.risk.o.acquiring.inection.i.still.breasteeding.

c. In.children.older.than.18.months.antibody.testing.is.denitived. Usually.HIV.antibody.testing.rom.9-18.months.o.agee. Where.virological.testing.is.not.readily.available.HIV.antibody.testing. should.be.perormed,.it. may.be.necessary. to.make.a.

presumptive.clinical.diagnosis.o.severe.HIV.disease.in.HIV.seropositive.children.(see.Box.1).Conrmation.o.diagnosis.should.be.sought.as.soon.as.possible

Non breastfed child Breastfed child

Diagnostic virological test from 6 weeks of age

Positive test result Negative test resultNegative test result

Child is uninfected Child is infected Child remains at risk ofacquiring HIV infection

until complete cessationof breastfeeding

a

Refer for HIV treatment andcare including initiation of ART

Child develops signs or symptoms suggestive of HIV Child remains well

Diagnostic HIV testingb,c

Routine follow-uptesting as per national

programmerecommendationsd

Virological test notreadily available

HIV antibody test eVirological test positive

HIV antibody positive andPresumptive severe HIV disease

Refer for assessment for HIV treatment and care including initiation of ART

Child is infected

Virological test availableNon.breased.

Breasted


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The. decision-making. process. or. initiating. ART. in.inants.and. children. relies. on. clinical. and.

immunological. assessment. In. order. to. acilitate. scale-up. to. universal. access. to. ART,. WHO.emphasizes.the.importance.o.clinical.parameters.This.approach.aims.at.enabling.all.children.needing.treatment.to.receive.it,.even.i.the.diagnosis.o.HIV.is.presumptive.and.i.CD4.is.not.available. However,. where. possible,. using. the. results. o. CD4. measurement. is. valuable,.particularly. or. decisions. about. starting. therapy. in. less. sick. children,. and. WHO.encourages.national.programmes.to.increase.access.to.CD4.measurement.technologies.Decision-making.about.starting.treatment.is.particularly.important.or.children.aged.under.12.months.as.the.probability.o.death.in.untreated.HIV-inected.children.is.high:.mortality.rates.o.up.to.40%.by.the.age.o.1.year.have.been.reported.(2,3,39,40).

The.decision.about.when.to.start.ART.should.also.involve.evaluation.o.the.social.environment.o.the.child.who.may.need.therapy.This.should.include.the.identication.o.a.clearly.dened.caregiver.who.understands.the.prognosis.o.HIV.and.the.implications.o.ART.(ie.lielong.therapy,.non-adherence,.administration,.toxicities.and. storage.o. drugs).Access.to.nutritional.support.(see.Section.XIII).and.amily.support.groups,.preerably.including.the.identication.o.a.secondary.(back-up).inormed.caregiver.is.advised.The.status.o.disclosure.to.the.child.and.among.the.amily.are.also.important.when.making.decisions.about.the.initiation.o.ART

Clinical assessment o HIV-inected children

The.WHO.Paediatric.Clinical.Classication.o.HIV-related.disease.has.recently.been.revised.and.is.now.harmonized.with.the.adult.classication.system.(Table.3)

Table 3. WHO classication o HIV-associated clinical diseasea

Classication o HIV-associated clinical disease WHO clinical stage

Asymptomatic 1

Mild 2

Advanced 3

Severe 4

a. Annex.B.provides.urther.details.on.staging.events.and.criteria.or.recognizing.them

Clinical. staging. is. or. use. where. HIV. inection. has. been. conrmed. (ie. serological. and/or.virological.evidence.o.HIV.inection).It.is.inormative.or.assessment.at.baseline.or.entry.into.HIV.care.and.can.also.be.used.to.guide.decisions.on.when.to.start.CPT.in.HIV-inected.children.and.other. HIV-related. interventions,. including. when. to. start,. switch. or. stop. ART. in. HIV-inected.children,.particularly.in.situations.where.CD4.is.not.available.Annex.B.provides.urther.details.o.

the.specic.staging.events.and.the.criteria.or.recognizing.them

A. preliminary. analysis. o. the. revised. WHO. staging. based. on. clinical. signs. at. baseline. and.disease.history.in.children.enrolled.in.the.Children.with.HIV.Antibiotic.Prophylaxis.(CHAP).trial.

V. WHEN TO START ANTIRETROVIRAL THERAPYIN INFANTS AND CHILDREN


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(41).showed.that.clinical.stage.without.ART.can.predict.mortality.However,.this.was.dependent.

on.the.malnutrition.criteria.in.the.staging.denitions.(D.Gibb,.unpublished.observations,.2005).The.clinical.stage.thereore.indicates.the.urgency.with.which.to.start.ART. (Table.4).Treatment.with.a.potent.and.ecient.ARV.regimen.improves.clinical.status.and.eectively.reverses.the.clinical.stage.There.is.an.urgent.need.or.studies.on.the.use.o.clinical.criteria.(ie.clinical.staging.events.on.treatment).or.when.to.switch.the.ARV.regimen.in.the.absence.o.viral.load.testing.(see.Section.X).

Immunological assessment o HIV-inected children

It.is.also.possible.to.measure.the.immunological.parameters.o.the.HIV-inected.child.and.assess.the.severity.o.HIV-related.immunodeciency.in.order.to.guide.decision-making.on.the.initiation.o.ART.The.results.o.CD4.measurement.should.be.used.in.conjunction.with.clinical.assessment.The.CD4.and.the.total.lymphocyte.count.(TLC).in.healthy.inants.who.are.not.inected.with.HIV.are.considerably.higher.than.those.observed.in.uninected.adults.and.slowly.decline.to.adult.values.by.the.age.o.about.6.years;.percentage.CD4+.(ie.%CD4+).values.vary.less.with.age.In.considering.the.results.o.immunological.parameters,.age.must.thereore.be.taken.into.account.as.a.variable.In.children.under.5.years.o.age.the.absolute.CD4.count.tends.to.vary.within.an.individual.child.more.than.%CD4+.Currently,.thereore,.the.measurement.o.%CD4+.is.thought.to. be.more.valuable. in.children. under.5. years.o. age.Absolute.CD4. counts.and,. to.a. lesser.

extent,.%CD4+.values,.fuctuate.within.an.individual.and.values.can.vary.with.intercurrent.illness,.physiological.changes,.timing.o.test.or.test.variability.Serial.measurements.are.thereore.more.inormative. than. individual. values. and. also. refect. trends. over. time. Where. possible,. these.assessments.should.compare.the.same.parameter;.ie.either.absolute.CD4.count.or.%CD4+.As. with. clinical. status,. immunological. recovery. occurs. with. successul. ART. Because. o. the.variability. o. both. absolute. CD4. counts. and. %CD4+,. two. values. below. threshold. should,. i.possible,. be. obtained. beore. the. initiation. o. ART. based. on. immunological. criteria. alone,.particularly.beore.starting.a.child.on.ART.with.no.or.mild.symptoms.o.HIV.(ie.clinical.stages.1.and.2).(5,.42-44).The.results.o.CD4.measurement.are.also.useul.or.monitoring.response.to.

treatmentThe.threshold.CD4.levels.or.severe.immunodeciency.(ie.


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3

mm3.or.inants.aged.


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Table 4. Recommendations or initiating ART in HIV-inected inants and children

according to clinical stage and availability o immunological markers

WHOpaediatric

stage

Availabilityo CD4 cell

measurements

Age-specic treatment recommendation

[A (II)]*

2 months

4a CD4 bTreat.all

No.CD4

3a CD4 b Treat.all Treat.all,.CD4-guided.in.those.children.

with.TB,c.LIP,.OHL,.thrombocytopenia

No.CD4 Treat.allc

2 CD4 b CD4-guidedd

No.CD4 TLC- guided d

1 CD4b

CD4-guidedd

No.CD4b Do.not.treat

*. Strength.o.recommendation/level.o.evidencea. Stabilize.any.opportunistic.inection.beore.initiation.o.ARTb. Baseline.CD4.is.useul.or.monitoring.ART.even.i.it.is.not.required.to.initiate.ARTc. In.children.with.pulmonary.or.lymph.node.tuberculosis.the.CD4.level.and.clinical.status.should.be.used.to.determine.the.need.or.

and.timing.o.initiation.o.ART.in.relation.to.tuberculosis.treatment.(see.Section.XII)d. Reer.to.Table.5.or.CD4.and.table.6.or.TLC.values

Table . CD4 criteria or severe HIV immunodeciency

Immunologicalmarkera

Age-specic recommendation to initiate ART b[A (I)]*

years

%CD4+c


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Table . TLC criteria or severe HIV immunodeciency requiring initiation o

ART; suggested or use in inants and children with clinical stage 2and where CD4 measurement is not available

Immunologicalmarkera

Age-specic recommendation to initiate ART b[C (II)]*


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AntiretrovirAl therApy of hiv infection in infAnts And children:


Box.1.lists.the.criteria.or.the.presumptive.clinical.diagnosis.and.Box.2.summarizes.the.WHO.

recommendations.or.starting.ART.in.inants.and.children

Box . Criteria or presumptive diagnosis o severe HIV disease in inants and

children aged under 8 months in situations where virological testing

is not available

[B (IV)]*

A.presumptive.diagnosis.o.severe.HIV.disease.should.be.made.i :. the.inant.is.conrmed.as.being.HIV.antibody-positive.

and

. diagnosis.o.any.AIDS-indicator.condition(s)a.can.be.made..or

. the.inant.is.symptomatic.with.two.or.more.o.the.ollowing:.. oral.thrush;b

. severe.pneumonia;b

. severe.sepsisbOther.actors.that.support.the.diagnosis.o.severe.HIV.disease.in.an.HIV-seropositive.inant.include:

. recent.HIV-related.maternal.death.or.advanced.HIV.disease.in.the.mother;.. %CD4+.


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Box 2. Summary o WHO recommendations or ART initiation in inants and

children

1. Inants.and.children.with.established.HIV.inection.(as.per.Section.IV).should.be.started.on.ART.i.they.have:.

. WHO.paediatric.clinical.stage.4.disease.(irrespective.o.CD4);

. WHO.paediatric.clinical.stage.3.disease.(irrespective.o.CD4,.although.it.may.add.guidance);.or.children.aged.over.12.months.with.tuberculosis,.lymphocytic.interstitial.pneumonia,.oral.hairy.leukoplakia.or.thrombocytopaenia,.ART.initiation.

may.be.delayed.i.CD4.is.available.and.above.threshold.valuesa.or.initiating.ART;.

. WHO.paediatric.clinical.stage.2.disease.and.CD4.or.TLCb.value.at.or.below.threshold;a

. WHO.paediatric.clinical.stage.1.disease.and.CD4.value.at.or.below.thresholda.

2. I.virological.testing.is.not.available.to.conrm.HIV.inection,.HIV.antibody-positive.inants.and.children.aged.under.18.months.should.be.considered.or.ART.i.they.have.clinically.diagnosed.presumed.severe.HIV.diseasec.

a. Threshold.values.or.CD4.are.provided.in.Table.5

b. Threshold.values.or.TLC.are.provided.in.Table.6.TLC.is.useul.or.decision-making.or.o.inants.and.children.with.clinical.stage.2.and.should.only.be.considered.where.CD4.measurement.is.not.available

c. Criteria.or.clinical.diagnosis.o.presumptive.severe.HIV.disease.are.provided.in.Box.1


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Considerations or treatment using a public health approach

Countries.are.encouraged.to.use.a.public.health.approach.to.support.and.acilitate.wider.access.to.ART.Among.the.key.tenets.o.this.approach.are.standardization.and.simplication.o.ARV.regimens.It.is.thereore.suggested.that.countries.select.a.limited.number.o.rst-line.regimens.and.suitable.second-line.regimens,.recognizing.that.individuals.who.cannot.tolerate.or.ail.the.rst-line.and.second-line.regimens.may.require.input.rom.more.experienced.physicians.The.use.o.three.ARV.medications.is.currently.the.standard.treatment.or.HIV.inection.in.order.to.achieve.the.best.possible.suppression.o.viral.replication.and.to.arrest.the.progression.o.HIV.disease. It. is. important. to. maximize. the. durability. and. ecacy. o. any. rst-line. regimen. by.

incorporating.approaches.to.support.adherence.When.appropriate.ARV.regimens.are.being.selected.or.the.national.ormulary,.programme-level.actors.should.be.taken.into.consideration.These.include:.

. ability.to.treat.all.ages;

. suitability. o.drug. ormulation,. particularly. or. inants. and. young.children.and. caregivers,.including,.where.possible,.licensing.approval.by.national.drug.regulatory.authorities.or.the.product.and.the.recommended.dose;

. toxicity.prole,.including.teratogenicity;.

. laboratory.monitoring.requirements;

. potential.or.maintenance.o.uture.treatment.options;.

. anticipated.patient.adherence.(including.consideration.o.drug.regimens.taken.by.parents.or.caregivers,.as.appropriate);.

. prevalent.coexisting.conditions.(eg.coinections,.malnutrition,.malaria,.TB,.possibly.hepatitis.B.and.C);.

. availability.and.cost-eectiveness;

. capacity.o.drug.procurement.and.supply.systems

The.choice.o.an.appropriate.ARV.regimen.may.be.urther.infuenced.by:.access.to.a.limited.number.o.ARV.drugs.in.orms.suitable.or.the.treatment.o.inants.and.young.children.(see.special.considerations.below);.limited.health.service.inrastructures.(including.human.resources);.and.the.presence.o.varied.HIV.types.(eg.HIV-2)

VI. WHAT TO START RECOmmENDED FIRST-LINE ARVREGImENS IN INFANTS AND CHILDREN


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Considerations or drug ormulations and doses or children

Quality-assured(i).ARV.drugs.in.xed-dose.combinations.(FDCs),(ii).or.blister.packs(iii).are.mostly.used.in.adults.and.older.children.It.is.to.be.hoped.that.they.increasingly.become.available.in.the.uture.or.administration.to.younger.children.Once-daily.dosing.has.become.available.or.some.adult. ARV. combinations. and. urther. simplies. drug. regimens. The.advantages. o.FDCs.and.once-daily. dosing.include. improved. adherence. which,.in. turn,. limits. the.emergence. o. drug.resistance.and.simplies.ARV.storage.and.distribution.logistics.

WHO strongly encourages the development o ormulations appropriate or paediatric use,

particularly solid ormulations (e.g. crushable, dispersible, granular, scored tablets or capsules

that can be opened) in doses that can be used by paediatric patients under 14 kg.

Syrups.and.solutions.remain.necessary.or.treating.inants.and.very.young.children.who.cannot.swallow. whole. tablets. or. capsules. but. they. have. shortcomings,. which. may. include. limited.availability,.high.cost,.storage.diculties,.reduced.shel-lie,.alcohol.excipient.and.poor.palatability.As. children. become. older. it. is. preerred. to. give. solid. ormulations. (par ts. o. scored. tablets. or.combination.preparations;.see.WHO/UNICEF.meeting.report.on.paediatric.ARV.ormulations.at.

http://wwwwhoint/3by5/paediatric/en/indexhtml). For. some. ARVs,. capsules. and. tablets. are.available.in.suciently.low.doses.to.enable.accurate.dosing.or.children.The.pharmacokinetics.o.some.crushed.tablets.or.sprinkled.capsule.contents.have.been.evaluated.However,.many.drugs.do.not.have.solid.ormulations.in.doses.appropriate.or.paediatric.use,.and.some.solid.ormulations.do. not. have. all. the. drug. components. evenly. distributed. in. the. tablets,. while. others. lack.pharmacokinetic. data. to. enable. accurate. dosing. National. drug. regulatory. authorities. should.consider.these.actors.when.making.decisions.on.licensing.products.or.use.in.children.

While.satisactory.virological.and.immunological.benets.in.children.receiving.an.adult.xed-dose.combination.o.stavudine/lamivudine/nevirapine.(d4T/3TC/NVP).tablets.in.ractions.were.reported.

rom.Thailand.(48).and.Uganda.(49),.the.use.o.tablets.that.require.cutting.up,.particularly.unscored.tablets,.can.result.in.the.underdosing.or.overdosing.o.children,.and.this.may.lead.to.an.increased.risk.o.resistance.or.toxicity.Moreover,.the.doses.cannot.easily.be.adjusted.as.the.children.grow,.which.may.urther.contribute.to.underdosing.The.splitting.o.adult-dose.solid.ormulation.ARVs,.while.suboptimal,.may,.however,.be.the.only.currently.available.option.or.the.treatment.o.children.as.soon.as.easible.(usually.when.a.weight.o.1012.kg.is.achieved),.and.may.be.considered.when.no.alternatives.are.available.The.use.o.tablet.cutters.is.benecial.but.it.is.preerable.not.to.cut.tablets.to.ractions.below.a.hal.Pharmacokinetic.studies.in.Malawian.children.conrm.that.the.use.o.single-drug.liquid.ormulations.is.better.than.splitting.adult.FDCs.or.smaller.children.(50).

(i). In.the.context.o. this. document,.quality-assured. medicines.assembled. in.xed-dose.combinations. (FDCs). include.individual.products.deemed.to.meet.international.standards.or. quality,.saety.and.ecacy.For.WHOs.work.on.the.prequalication.o.ARVs,.see:.http://wwwwhoint/3by5/amds/en/

(ii). FDCs.include.two.or.more.active.pharmacological.produ cts.in.the.same.pill,.capsule,.granules,.tablet.or.solution

(iii). A.blister.pack.is.a.plastic.or.aluminium.blister.containing.two.or.more.pills,.capsules.or.tablets


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Dosing.in.children.is.usually.based.on.either.body.surace.area.or.weight.(51).As.these.change.

with. growth,. drug. doses. must. be. adjusted. in. order. to. avoid. the. risk. o. underdosage.Standardization.is.important.and.it.is.desirable.to.provide.health.care.workers.with.tables.o.simplied.drug. doses. that. can.be. administered. Such. tables.may. vary.between.localities. in.accordance.with.the.availability.o.ARV.drugs.and.ormulations.in.the.countries.concerned.WHO.has.developed.prototype.dosing.tables.based.on.weight,.and.tools.to.assist.countries.with.the.standardization.and.calculation.o.drug.doses (i )(Annex.E).Fixed-dose.ormulations.or.children.became.available.in.late.2005;.they.include.d4T/3TC/NVP.in.dierent.strengths

FDC o standard frst and second line ARV regimens are urgently needed or younger children.

Considerations or the choice o a rst-line regimen

Studies.o.antiretroviral.therapy.in.children.demonstrate.that.similar.improvements.to.those.obtained.in.adults.are.seen.in.morbidity,.mortality.and.surrogate.markers.with.many.dierent.potent.ARV.regimens.(39,.52-55).The.preerred.option.when.choosing.a.rst-line.regimen.or.inants.and.children.is.two.nucleoside. reverse. transcriptase. inhibitors. (NRTIs). plus. one. non-nucleoside. reverse. transcriptase.inhibitor.(NNRTI).(Box.3).These.drugs.prevent.HIV.replication.by.inhibition.o.the.action.o.reverse.

transcriptase,.the.enzyme.that.HIV.uses.to.make.a.DNA.copy.o.its.RNA.The.technical.reerence.group.based.this.decision.on.available.evidence,.clinical.experience.and.programmatic.easibility.or.the.wider. introduction. o. ART. to. inants. and. children. in. resource-limited. settings. NRTI/NNRTI-based.regimens.are.ecacious.and.generally.less.expensive;.generic.ormulations.are.more.oten.available.and.a.cold.chain.is.not.required.In.addition,.they.preserve.a.potent.new.class.(ie.protease.inhibitors.[PIs]).or.the.second.line.The.disadvantages.include.dierent.hal-lives,.the.act.that.a.single.mutation.is.associated.with.resistance.to.some.drugs.(eg.lamivudine.[3TC],.NNRTIs),.and,.in.respect.o.the.NNRTIs,.a.single.mutation.can.induce.resistance.to.all.currently.available.drugs.in.the.class.

Active.components. o. these. regimens. may. include. a. thymidine.analogue. NRTI. (ie.stavudine.

[d4T],.zidovudine.[AZT]).or.a.guanosine.analogue.NRTI.(ie.abacavir.[ABC]),.combined.with.a.cytidine. analogue. NRTI,. (ie. lamivudine. [3TC]. or. emtricitabine. [FTC]). and. an. NNRTI. (ie.eavirenz.[EFV].or.nevirapine.[NVP]).A.caveat.is.that.EFV.is.not.currently.recommended.or.use.in.children.under.3.years.o.age.because.o.a.lack.o.appropriate.dosing.inormation,.although.these. matters. are. under. study. For. such. children,. consequently,. NVP. is. the. recommended.NNRTI.Additional.concerns.about.NNRTIs.as.components.o.rst-line.regimens.relate.to.their.use.in.adolescents.(see.Section.XIV);.these.include.the.teratogenic.potential.o.EFV.in.the.rst.trimester.o.pregnancy.and.the.hepatotoxicity.o.NVP.in.adolescent.girls.with.CD4.absolute.cell.counts.>250/mm3.The.available.data.on.inants.and.children.indicate.a.very. low.incidence.o.

severe.hepatotoxicity.or.NVP.without.association.with.CD4.count.(56)

(i). A.web-based.tool.to.assist.in.development.o.dosing.tables.or.national.programmes.is.available.on.the.WHO.website.http://wwwwhoint/paediatric/en/indexhtml


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Box 3. Summary o recommended preerred rst-line ARV regimens or

inants and children

Regimen o 2 NRTI plus NNRTIa

[A.(II)]*

A Z T b.+.3TC c.+.NVP d/ EF V e

d4T b.+.3TC c.+.NVP d/E F V e

ABC.+.3TC c.+.NVP d/ EF Ve

*. Strength.o.recommendation/level.o.evidencea. The.use.o.AZT,.d4T,.ABC.with.3TC.results.in.several.possible.dual.nucleoside.combinations.(see.ollowing.section.on.choice.o.

NRTI)b. AZT.should.not.be.given.in.combination.with.d4T.c. Where.available,.FTC.can.be.used.instead.o.3TC.in.children.over.3.months.o.aged. NVP.should.be.used.with.caution.in.postpubertal.adolescent.girls.(considered.as.adults.or.treatment.purposes).with.baseline.

CD4.absolute.cell.counts.>250/mm3e. EFV.is.not.currently.recommended.or.children.under.3.years.o.age.and.should.be.avoided.in.postpubertal.adolescent.girls.who.

are.either.in.the.rst.trimester.o.pregnancy.or.are.sexually.active.and.not.receiving.adequate.contraception.

The.use.o.a.triple.NRTI.regimen.(ie.AZT/d4T.+.3TC.+.ABC).can.be.considered.as.an.option.or.

simpliying.initial.therapy.in.special.circumstances.(Box.4).A.concern.is.the.somewhat.lower.virological. potency. o. this. regimen. compared. to. a. two-class. triple. drug. combination. in. adult.studies.(57-60).and.thereore.its.use.is.currently.restricted.to.special.circumstances,.in.particular.or.inants.and.children.receiving.TB.treatment,.a.situation.where.NVP.may.not.be.an.optimal.choice.because.o.drug.interactions.with.riampicin.(see.Section.XII).Another.possible.indication.or.the.use.o.a.triple.NRTI.regimen.is.the.treatment.o.pregnant.adolescent.girls.with.CD4.absolute.cell.counts.>250/mm3.This.regimen,.especially.where.combined.in.a.single.pill,.could.also.be.considered.in.adolescents.with.anticipated.or.documented.poor.adherence.(see.Section.XIV).

Box 4. Recommended alternative ARV regimen or inants and children to

simpliy management o toxicity, comorbidity and drug-drug interaction

Regimen o triple NRTI

[C.(III)]*

AZT/d4Ta.+.3TCb.+.ABC

*. Strength.o.recommendation/level.o.evidencea. AZT.should.not.be.given.in.combination.with.d4Tb. Where.available,.FTC.can.be.used.instead.o.3TC.in.children.over.3.months.o.age


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Choice o NRTIs

The.drugs.rom.the.NRTI.class.recommended.or.children.within.the.public.health.approach.are.described.below

Lamivudine (3TC),.is.a.potent.NRTI.with.an.excellent.record.o.ecacy,.saety.and.tolerability.in.HIV-inected.children.and.is.a.core.component.o.the.dual.NRTI.backbone.o.therapy.It.is.usually.given.twice.daily.in.children.and.has.been.incorporated.into.a.number.o.FDCs.

Emtricitabine (FTC).is.a.newer.NRTI.that.has.recently.been.included.in.WHOs.recommended.rst-line. regimens. or. adults. as. an. option. and. is. also. available. or. use. in. children. FTC. is.

structurally.related.to.3TC.and.shares.its.resistance.prole.(61).Where.available.it.can.be.used.in.children.over.3.months.o.age.as.an.alternative.to.3TC

The.choice.between.d4T,.AZT.or.ABC.to.be.combined.with.3TC.should.be.made.at.the.country.level.on.the.basis.o.local.considerations.but.it.is.recommended.that.at.least.two.o.these.NRTIs.be.available.to.allow.the.substitution.o.one.drug.or.the.other.should.there.be.toxicity.

Stavudine (d4T). is. an. NRTI. that. is. initially. better. tolerated. than. AZT. and. does. not. require.haemoglobin.or.laboratory.monitoring.However,.among.the.NRTIs.it.has.been.consistently.most.associated.with.lipoatrophy.(62).and.lactic.acidosis.In.addition,.elevated.hepatic.transaminases.and. pancreatitis. have. been. observed. d4T. can. also. cause. peripheral. neuropathy,. although.

these.complications.appear.to.be.less.common.in.children.than.in.adults.(63,.64).d4T.liquid.ormulations.require.a.cold.chain.and.the.capsule.size.starts.at.15.mg.only.While.ewer.laboratory.monitoring. requirements.may.be.a. good.reason.to.avour. d4T. over. AZT. as.the.chosen. NRTI.component,.in. particular. during. the.rapid.scale-up. o. programmes,. the. considerable. risk. o.lipoatrophy. in. children. treated. with. d4T-containing. regimens. remains. National. programmes.may.thereore.need.to.take.into.account.the.comparative.short-term.and.long-term.toxicities.o.rst-line.options.(see.Section.VIII).and.introduce.measures.or.the.close.monitoring.o.drugs.associated.with.an.increased.risk.or.toxicities.It.is.worth.emphasizing.that.d4T.and.AZT.should.never.be.used.together.because.o.proven.antagonism.between.them.(65,.66).(Box.5).

Zidovudine (AZT).is.generally.well.tolerated.in.children.but.has.been.associated.with.metabolic.complications.o.therapy,.although.to.a.lesser.extent.than.d4T.Initial.drug-related.side-eects.are. more. requent. with. AZT. and. the. drug. can. cause. severe. anaemia. and. neutropenia;.haemoglobin.monitoring.beore.and.during.treatment.with.AZT.is.thus.useul.This.is.particularly.important.in.areas.with.stable.malaria.or.where.malnutrition.is.common.and.anaemia.is.highly.prevalent.in.young.children.Large.volumes.o.AZT.liquid.ormulation.are.oten.poorly.tolerated.d4T.can.be.substituted.or.AZT.in.the.event.o.intolerance.to.the.latter.and.vice.versa,.except.in.cases.o.suspected.lactic.acidosis,.where.neither.drug.should.be.restarted.As.noted.above,.AZT.should.not.be.administered.in.combination.with.d4T

Abacavir (ABC),.has.been.included.in.these.revised.paediatric.guidelines.as.an.alternative.NRTI.in.rst-line.therapy,.representing.a.change.rom.the.2003.guidelines.that.recommended.reserving.the.use.o.ABC.as.part.o.second-line.regimens.Clinical.trial.results.in.antiretroviral-naive.persons.demonstrating.ecacy,.availability.o.ABC.in.paediatric.ormulation,.and.the.resulting.potential.to.


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23

deliver. amily-based. care. o.HIV-inected. parents. and.children. with. ABC/3TC,. oset. concerns.

about.introducing.an.additional.rst-line.drug.Reports.rom.a.randomized,.partly.blind.multicentre.trial.comparing.dual.NRTI.regimens.(PENTA-5).(67).have.shown.that.ABC-containing.dual.NRTI.regimens.(ABC/3TC.or.ABC/AZT).are.more.eective.than.regimens.containing.AZT.+.3TC.in.children.with.HIV-1.who.have.not.been.previously.treated.The.results.have.also.suggested.a.similar.saety.prole.in.children.to.that.in.adults,.with.very.little.haematological.toxicity.NRTI.combinations.containing.ABC.thereore.provide.a.good.NRTI.backbone.or.use.with.NNRTIs.or.as.part.o.a.triple.nucleoside.regimen.O.all.the.NRTI.drugs,.ABC.has.the.least.eect.on.mitochondrial.DNA.(68).and.would.be.the.preerred.substitute.or.d4T.in.children.developing.lactic.acidosis.while.receiving.a.d4T-containing. regimen. ABC. could. also. be. substituted. or. AZT. in. the. event. o. intolerance.

However,.ABC.is.associated.with.a.potentially.atal.hypersensitivity.reaction.in.about.3%.o.children.who.receive.it.(67).In.inants.and.children.suspected.o.having.a.hypersensitivity.reaction,.ABC.should.be.stopped.and.not.restarted.(see.Section.VIII).Children.and/or.their.caregivers.should.be.advised.about.the.risk.o.this.serious.hypersensitivity.reaction.and.the.need.to.consult.their.care.provider.immediately.i.signs.or.symptoms.o.a.hypersensitivity.reaction.occur.

Tenoovir (TDF),.is.another.drug.that.has.been.incorporated.as.an.eective.option.or.rst-line.regimens.in.adults.Because.o.concerns.about.the.limited.data.on.saety.and.toxicity.(ie.bone.mineralization.and.potential.renal.toxicity).the.use.o.TDF.in.children.is.not.encouraged.until.urther.data.become.available.TDF.is.generally.well.tolerated.(69),.although.there.have.been.

reports.o.renal.insuciency.in.adult.patients.receiving.it.(70-72).A.study.in.16.HIV-inected.children.(age.range.64.to.179.years).on.12-month.treatment.comparing.TDF.and.d4T.reported.that. TDF. did. not. impair. bone. mineral. accrual. while. demonstrating. a. good. immunological.response. to. ART. (73). However,. a. paediatric. study. in. HIV-inected. antiretroviral-experienced.children.(age.range.83.to.162.years).demonstrated.a.decrease.o.more.than.6%.in.bone.mineral.density.in.about.30%.o.those.evaluated.ater.48.weeks.o.TDF.therapy,.thus.potentially.limiting.the.use.o.TDF.among.prepubertal.children.(74).

Didanosine (ddI).is.an.adenosine.nucleoside.analogue.NRTI.Its.use.is.usually.reserved.or.second-line.regimens.(see.Section.XI).


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Box.5.Summarizes.the.NRTI.drug.combinations.that.should.be.avoided.

Box . NRTI drug combinations to be avoideda

. d4T.+.AZT.-.both.drugs.work.through.common.metabolic.pathways.[A(I)]*

.d4T.+.ddIb.-.these.drugs.have.overlapping.toxicities.[A(I)]*.TDF.+.3TC.+.ABCc.

.TDF.+.3TC.+.ddId.

.TDF.+.ddI.+.NNRTIe

these.regimens.are.associated.with.a.high.incidence.o.early.virologic.ailure.[A(III)].*

*. Strength.o.recommendation/level.o.evidencea. Based.on.data.rom.studies.perormed.in.adultsb. Didanosine.(ddI).is.an.adenosine.analogue.NRTI.which.is.generally.reserved.or.second-line.regimens.(see.Section.XI).c. Data.rom.three.clinical.trials.in.adults.involving.the.combination.o.TDF.+.3TC.+.ABC.demonstrated.high.rates.o.virological.

ailure.and.drug.resistance.Given.these.concerns.and.the.lack.o.clinical.data,.this.NRTI.backbone.should.not.be.used.in.treatment-nave.patients.Another.report.conrms.that.ABC.and.TDF.select.or.the.K65R.mutation,.which.reduces.susceptibility.to.both.drugs.(75).

d. A.pilot.study.using.this.regimen.resulted.in.a.high.incidence.o.K65R.mutation.and.virologic.ailure.(76).e. Source:.reerences.(77-80)

Choice o NNRTIs

NNRTI-based.regimens.are.now.the.most.widely.prescribed.combinations.or.initial.therapy.They.are.potent,.ie.they.rapidly.reduce.the.viral.load,.but.are.inactive.with.respect.to.HIV-2.and.group.O.o.HIV-1,.and.a.single.mutation.can.induce.cross-class.resistance.The.NNRTIs.eavirenz.(EFV). and. nevirapine. (NVP). have. both. demonstrated. clinical. ecacy. when. administered. in.appropriate. combination. regimens. in. children. However,. dierences. in. toxicity. prole,. the.potential. or. interaction. with. other. treatments,. a. lack. o.dosing. inormation. or. EFV. in.young.children,.and.cost.are.actors.that.need.to.be.taken.into.consideration.when.choosing.an.NNRTI.(81-88)

Eavirenz (EFV).is.not.currently.recommended.or.use.in.inants.and.children.under.3.years.o.age.because.there.is.no.established.dosing.EFV.is.primarily.associated.with.toxicities.related.to.the.central.nervous.system.(CNS),.teratogenicity.and.rash.Rash.is.more.requent.in.children.than.adults,. is. generally. mild,. and. usually. does. not. require. discontinuation. o. therapy. The. CNS.symptoms.typically.abate.ater.10.to.14.days.in.the.majority.o.patients;.observational.studies.have.revealed.transient.CNS.disturbance.in.26%.to.36%.o.children.receiving.EFV.(55,.88).EFV.should.be.avoided.in.children.with.a.history.o.severe.psychiatric.illness,.where.there.is.a.potential.or.pregnancy.(unless.eective.contraception.can.be.assured).and.during.the.rst.trimester.o.pregnancy.In.these.situations,.NVP.may.be.the.better.choice.(see.below).EFV.may.be.considered.as.the.NNRTI.o.choice.in.children.with.TB/HIV.coinection.(see.Section.XII)

Nevirapine (NVP).should.only.be.given.in.combination.with.other.antiretrovirals,.except.when.used.or.single-dose.prophylaxis.to.reduce.the.risk.o.perinatal.HIV.transmission.NVP.has.a.higher.incidence.o.rash.than.other.ARVs.NVP-related.rash.may.be.severe.and.lie-threatening,.including.Stevens-Johnson.syndrome,.and,.as.noted.above,.NVP.is.also.associated.with.a.rare.


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2

but. potentially. l ie-threatening. risk. o. hepatotoxicity. In. these. situations,. NVP. should. be.

permanently.discontinued.and.not.restarted.(see.Sections.VIII.and.IX).This.makes.the.drug.less.suitable.or.treating.children.who.use.other.hepatotoxic.medications,.or.drugs.that.can. cause.rash,.or.both,.such.as.riampicin.or.the.treatment.otuberculosis.There.are.limited.data.on.the.use.o.NVP.in.children.coinected.with.HIV.and.hepatitis.B.NVP.is.currently.the.only.NNRTI.syrup.available. or. inants. It.also.exists.as.part. o.three-drug. FDCs. which.could.be. used.or. older.children.when.quality-assured.ormulations.o.proven.bioequivalence.are.available

NVP.may.be.the.preerred.choice.in.adolescent.girls.when.there.is.potential.or.pregnancy,.or.during.the.rst.trimester. o.pregnancy. when. EFV.should. be.avoided.because. o.its.potential.teratogenic.eect.However,.symptomatic.NVP-associated.hepatotoxicity.or.serious.rash,.while.

uncommon,.is.more.requent.in.women.than.in.men,.and.is.more.likely.to.be.seen.in.antiretroviral-naive.women.with.higher.CD4.cell.counts.(>250.cells/mm 3).Thus,.NVP.should.be.used.with.caution.in.adolescent.girls.with.CD4.counts.between.250.and.350.cells/mm 3;.i.used.in.such.adolescent.girls,.careul.monitoring.is.needed.during.the.rst.12.weeks.o.therapy,.preerably.including.liver.enzyme.monitoring.

Limited.data.indicate.that.both.EFV.and.NVP.may.interact.with.estrogen-based.contraceptive.pills.Because.exposure.to.EFV.should.be.avoided.in.the.rst.trimester.o.pregnancy.it.is.recommended.that. sexually. active. adolescent. girls. receiving. EFV. consistently. use. barrier. methods. to. prevent.pregnancy. in. addition. to. or. instead. o. oral. contraceptives. Studies. are. in. progress. to. evaluate.

interactions.between.medroxyprogesterone.acetate.and.selected.PI.and.NNRTI.drugs.

Annex. E. provides. more. detailed. inormation. on. dosing,. preparations,. storage. and. special.instructions.on.the.administration.o.the.above-listed.drugs

Use o protease inhibitors (PIs) in initial therapy

It.is.recommended.that.the.PI.class.o.drugs.be.reserved.or.second-line.therapy.because.the.use.o.PIs.in.an.initial.treatment.regimen.compromises.any.subsequent.second-line.regimen.Until.urther.data.become.available,.this.also.holds.true.in.situations.where.single-dose.NVP.has.

been.used.or.PMTCT.(see.Section.VII).Currently.available.PIs.are.described.in.more.detail.in.Section.XI.


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ART in inants exposed to ARVs through interventions

to prevent mother-to-child transmission

I.a.mother.has.received.ARVs.during.pregnancy,.either.or.prevention.o.transmission.o.the.virus.to.her.inant.or.or.her.own.disease,.there.is.a.possibility.that.the.inant.may.become.inected.with.drug-resistant.virus.Additionally,.resistance.could.be.induced.de.novo.in.an.inected.inant.who.is.exposed.to.an.ARV.drug.being.used.or.prevention.(ie.the.inant.component.o.MTCT).beore.the.inection.status.o.the.inant.is.known.This.is.a.particular.problem.i.NVP.or.3TC.has.been.used,.either.alone.or.as.a.component.o.a.two-drug.regimen,.or.prevention.o.MTCT,.because.a.single.point.mutation.is.associated.with.resistance.to.each.o.these.drugs.(89,.90).In.HIVNET.012,.

ollowing.single-dose.NVP,.46%.o.inected.inants.had.NNRTI-associated.mutations.(primarily.the.Y181C.mutation,.which.may.not.always.be.associated.with.cross-resistance.to.EFV ).As.has.been. observed. in. mothers,. these. mutations. ade. with. time. but. may. persist. as. minor. viral.subpopulations.(89).It.is.not.known.whether.ARV.choices.should.be.modied.or.inants.who.have.been.exposed.to.ARVs.used.or.PMTCT.Studies.in.children.are.in.progress.(ie.South.Arica.NEVEREST.study.and.Botswana).or.are.planned.(ie.multicountry.PACTG.1060),.as.they.are.in.mothers,.to.investigate.whether.single-dose.NVP.prophylaxis.compromises.subsequent.ART.with.NNRTI-based.regimens.WHO.recognizes.the.urgency.o.such.research.However,.until.there.are.data.allowing.these.questions.to.be.denitively.answered,.children.who.require.ART.and.who.have.previously.received.single-dose.NVP.or.3TC.as.part.o.PMTCT.should.be.considered.eligible.or.NNRTI-based.regimens.and.should.not.be.denied.access.to.lie-sustaining.therapy.

Ongoing exposure to ARVs due to maternal ART in breast eeding inants

The.penetration.o.ARVs.into.human.breast.milk.in.lactating.women.has.not.been.quantied.or.most.ARVs.Although.some.ARVs,.such.as.NVP,.AZT.and.3TC,.are.known.to.be.present.in.breast.milk,.the.concentration.and.quantity.o.drug.ingested.by.inants.would.be.less.than.those.needed.to.achieve.therapeutic.levels.(30,.81).Consequently,.i.a.breasteeding.inant.is.ill.enough.to.require. ART,. the. administration. o. ARVs. at. standard. paediatric. doses. should. be. initiated.

regardless.o.whether.the.mother.is.receiving.ART,.but.closer.monitoring.o.the.inant.or.potential.toxicity.should.be.considered.Because.o.the.benets.o.breastmilk,.continued.breasteeding.should.be.encouraged.In.addition,.it.is.possible.that.the.ingestion.o.subtherapeutic.levels.o.some.ARVs.by.breasteeding.inants.could.lead.to.the.development.o.drug.resistance.in.the.inants. virus,. diminishing. the. ecacy. o. the. prescribed. paediatric. regimen,. but. there. are.currently.insucient.data.to.make.recommendations.

Box.6.summarizes.the.recommendations.on.ART.in.inants.with.previous.or.continuing.exposure.to.ARVs.

VII. CONSIDERATIONS FOR ART IN INFANTS PREVIOUSLYExPOSED TO ARV DRUGS


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Box . Summary o recommendations on ART in inants and children

exposed to ARV drugs [B (IV)]*

. Inants.who.were.exposed.to.ARVs.or.prevention.o.mother-to-child.transmission,.either.the.maternal.or.inant.component,.and/or.

. Breasteeding.inants.who.are.exposed.to.antiretroviral.drugs.because.o.maternal.

ART

should.be.considered.eligible.or.the.standard.2.NRTIs.+.1.NNRTI.rst-line.ARV.regimen.using.the.same.doses.and.criteria.as.are.outlined.in.Sections.V.and.VI

Research.is.urgently.needed.to.identiy.the.ecacy.o.ART.in.inants.with.previous.or.continuing.exposure.to.ARVs.

*. Strength.o.recommendat ions/.level.o.evidence


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It.is.sometimes.dicult.to.dierentiate.between.complications.o.HIV.disease.and.toxicity.(also.

known.as.adverse.events).secondary.to.ARV.drugs.used.or.the.management.o.HIV.inection.or.drug-drug.interactions.Alternative.explanations.or.toxicity.must.be.excluded.beore.concluding.that.it.is.secondary.to.the.ARV.drugs.Such.explanations.or.an.observed.toxicity.could.include.a.concurrent.inectious.process.(eg.common.childhood.illnesses.including.hepatitis.A.virus.inection.in.a.child.with.symptoms.o.hepatitis,.or.malaria.in.a.child.with.severe.anaemia),.or.a.reaction.to.a.non-ARV.drug.that.is.being.given.concurrently.with.ARV.drugs.(such.as.isoniazid-induced.hepatitis.in.a.child.ontuberculosis.treatment.or.co-trimoxazole-induced.rash.in.a.child.receiving.CPT).Adverse.reactions.that.have.a.non-ARV.drug.etiology.do.not.require.the.ARV.drug.to.be.changed.However,.because.o.the.risk.o.potentially.lie-threatening.hepatotoxicity.

associated.with.NVP,.hepatic.dysunction.o.any.etiology.requires.careul.consideration.be.given.to.the.discontinuation.o.NVP.

Although.there.are.ewer.data.on.ARV.drug.toxicit y.in.children.than.in.adults,.the.ull.spectrum.o.ARV. toxicit ies. observed. in. adults. has. also. been. reported. in. children. (91). However,. some.toxicities.are.less.common.in.children.than.in.adults.(eg.NVP-related.symptomatic.hepatotoxicity.is.rare.in.children),.while.others.are.more.common.in.children.than.adults.(eg.EFV-related.rash).or.occur.only.in.children.(eg.TDF-related.loss.o.bone.density).More.attention.should.be.paid.to.pharmacovigilance.and.post-marketing.surveillance.in.paediatric.populations

Drug-related.adverse.events.may.be.acute,.occurring.soon.ater.a.drug.has.been.administered;.they.

may.be.subacute,.occurring.within.1.to.2.days.o.administration;.or.they.may.be.late,.occurring.ater.prolonged.drug.administration.Such.adverse.events.may.vary.in.severity.rom.mild.to.severe.and.lie-threatening.Experience.with.ARV.drugs.has.led.to.the.recognition.o.several.types.o.distinct.adverse.drug.eects.that.may.be.most.common.with.certain.ARV.drugs.or.drug.classes,.including:

. haematological.adverse.events.associated.with.drug-induced.bone-marrow.suppression,.most.commonly.seen.with.AZT.therapy.(anaemia,.neutropenia.and,.more.rarely,.thrombocytopenia);

. mitochondrial.dysunction,.primarily.seen.with.the.NRTI.drugs,.including.lactic.acidosis,.hepatic.toxicity,. pancreatitis. and. peripheral. neuropathy. (the. NRTIs. dier. in. their. ability. to. aect.

mitochondrial.unction,.d4T.having.greater.toxicity.than.AZT.and.3TC,.and.ABC.even.less.so);. lipodystrophy.and.metabolic.abnormalities,.primarily.seen.with.d4T.and.the.PI.class,.and.to.

a.lesser.degree.with.certain.other.NRTI.drugs.(abnormalities.include.at.maldistribution.and.body. habitus. changes,. hyperlipidaemia;. hyperglycaemia,. insulin. resistance,. diabetes.mellitus,.osteopaenia,.osteoporosis.and.osteonecrosis);

. allergic.reactions.such.as.skin.rashes.and.hypersensitivity.reactions,.more.common.with.the.NNRTI.drugs.but.also.seen.with.certain.NRTI.drugs,.such.as.ABC

Toxicity. can. be. monitored. clinically. on. the. basis. o. child/guardian. reporting. and. physical.

examination,. and. can. also. be. assessed. by. means. o. a. limited. number. o. laboratory. tests,.depending.on.the.specic.ARV.combination.regimen.that.is.utilized.and.the.health.care.setting.Routine.laboratory.monitoring,.although.desirable,.is.not.required.and.cannot.be.carried.out.in.many.decentralized.acilities

VIII. ANTIRETROVIRAL DRUG TOxICITY


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The.management.o.the.patient.and.the.decision.about.the.potential.need.to.stop.drugs.or.to.

substitute (i ).a.new.ARV.drug.or.a.drug.associated.with.toxicity.largely.depends.on.the.ability.to.attribute.the.toxicity.to.a.specic.ARV.drug.in.the.treatment.regimen.and.on.the.severity.o.the.toxicity. symptoms. (Box. 7). Given. the. limited. number. o. ARV. drugs. and. drug. combinations.available.in.resource-limited.settings,.it.is.preerable.to.pursue.drug.substitutions.where.easible.so.to.avoid.premature.switching.to.completely.new.alternative.regimens,.and.to.restrict.drug.substitutions.to.situations.where.toxicity.is.severe.or.lie-threatening.

As.a.general.principle, mild toxicities.do.not.require.discontinuation.o.therapy.or.drug.substi tution,.and.symptomatic.treatment.may.be.given.(eg.antihistamines.or.a.mild.rash).Some.moderate.or.severe.toxicities.may.require.the.substitution.o.an.ARV.drug.associated.with.toxicity.by.a.drug.

in.the.same.ARV.class.but.with.a.dierent.toxicity.prole.(eg.peripheral.neuropathy).or.by.a.drug.in.a.dierent.class,.but.do.not.require.discontinuation.o.all.ART. Severe lie-threateningtoxicity. requires.discontinuation. o.all. ARV.drugs. and. the. initiation. o.appropriate. supportive.therapy.(such.as.intravenous.fuids),.depending.on.the.toxicity,.with.substitution.o.another.drug.or.the.one.associated.with.the.toxicity.once.the.patient.is.stabilized.and.the.toxicity.is.resolved.(see.Annex.F).NNRTI.drugs.have.a.much.longer.hal-lie.than.NRTIs,.leading.to.a.concern.that.stopping. all. drugs. simultaneously. results. in. exposure. to. drugs. rom. the. NNRTI. class. only.However,.i.a.child.has.a.lie-threatening.toxicity,.all.ARV.drugs.should.be.stopped.simultaneously.until.the.patient.is.stabilized.

Clinical.examination.can.also.detect.toxicities.that.are.not.lie-threatening.and.that.may.appear.late.(months.to.years.ater.therapy.has.been.started),.such.as.lipodystrophy.In.such.cases,.reerral.or.management.to.district.or.regional.hospital.centres.or.consultation.with.an.HIV.expert.is.recommended.

Regardless. o. their. severity,. adverse. events. may. aect. adherence. to. therapy. A. proactive.approach.to.managing.toxicity.is.recommended.Discussing.the.potential.side-eects.o.the.ART. regimen. beore. the. init iation. o. therapy.and.during. the.ear ly. stages.o. treatment.with. the.child.and.her/his.caregivers.as.well.as.support.during.minor.and.moderate.adverse.events,.can.increase.the.likelihood.o.adherence.to.therapy.(see.Section.XVI).The.child.and.the.caregivers.

should.be.amiliar.with.signs.o.toxicities.that.are.serious.and.require.immediate.contact.with.the.provider.and.potential.drug.discontinuation.This.is.particularly.important.or.toxicities.that.can.be.lie-threatening.i.the.ARV.drug.is.not.discontinued,.such.as.the.NVP-associated.Stevens-Johnson.syndrome,.symptomatic.hepatitis.or.the.ABC-associated.hypersensitivity.reaction

(i). Substitution.is.the.exchange.o.one.drug.in.a.(rst-line).regimen.or.another.(rst-line.regimen).drug;.this.is.dierent.rom.switching.a.drug.because.o.ailure.when.all.drugs.o.a.regimen.are.changed.to.a.dierent.(second-line).regimen.(see.Sections.IX.and.X)


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Box . Guiding principles in the management o ARV drug toxicity

1. Determine.the.seriousness.o.the.toxicity

2. Evaluate.concurrent.medications.and.establish.whether.the.toxicity.is.attributable.to.an.ARV.drug.or.to.a.non-ARV.medication.taken.at.the.same.time

3. Consider.other.disease.processes.(eg.viral.hepatitis.in.a.child.on.ARV.drugs.who.develops.jaundice).or.immune.reconstitution.syndrome,.because.not.all.problems.that.arise.during.treatment.are.caused.by.ARV.drugs

4. Manage.the.adverse.event.according.to.severity.In.general:

. Severe.life-threatening.reactions.(Annex.F):.Immediately.discontinue.all.ARV.drugs,.manage.the.medical.event.(ie.symptomatic.and.supportive.therapy).and.reintroduce.ARV.drugs.using.a.modied.regimen.(ie.with.an.ARV.substitution.or.the.oending.drug).when.the.patient.is.stabilizeda

. Severe.reactions:.Substitute.the.oending.drug.without.stopping.ARTa.

. Moderate.reactions:.Consider.continuation.o.ART.as.long.as.easible.I.the.patient.does.not.improve.on.symptomatic.therapy,.consider.single-drug.substitutionsa.For.a.ew.moderate.toxicities.(eg.peripheral.neuropathy.or.lipodystrophy).single.drug.substitution.needs.to.be.considered.earlier

. Mild.reactions.are.bothersome.but.do.not.require.changes.in.therapy

5. Stress.the.maintenance.o.adherence.despite.toxicity.or.mild.and.moderate.reactions.

6. I.there.is.a.need.to.discontinue.ART.because.o.lie-threatening.toxicity,.all.ARV.drugs.should.be.stopped.until.the.patient.is.stabilized.

a. Reer.to.Table.7.or.substitution.options


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I.toxicity.is. related.to. an.identiable. drug. in.a. regimen. the. oending. drug. can. generally.be.

replaced.with.another.drug.rom.the.same.class.that.does.not.have.the.same.adverse.eect,.eg.substitution.o.d4T.or.AZT.(eg.or.anaemia).or.NVP.or.EFV.(eg.or.CNS.toxicity.or.in.the.event.o.pregnancy.in.adolescent.girls).Given.the.limited.number.o.ARV.drug.options.available.in.resource-limited. settings,. drug. substitutions. should. be. limited. to. situations. where. toxicity. is.severe.or.lie-threatening.(see.Annex.F).For.reasons.o.toxicity.the.substitution.o.drugs.rom.the.PI.class.should.be.avoided.i.possible.Table.7.lists.the.usual.ARV.substitution.options.or.adverse.events.or.the.recommended.combination.rst-line.regimens.

For.some.lie-threatening.toxicities.it.may.not.be.possible.to.identiy.an.optimal.substitute.drug.For.example,.in.respect.o.NVP-associated.Stevens-Johnson.syndrome,.most.clinicians.would.

avoid.substituting.another.NNRTI.drug.(eavirenz).because.o.the.potential.or.class-specic.toxicity.This.would.require.a.change.to.either.a.triple.NRTI.regimen.(eg.substituting.a.third.NRTI,. such. as.ABC,.or. NVP),.or. substituting. a.protease.inhibitor. ARV.drug.or. NVP,.thereby.introducing.a.drug.class.usually.reserved.or.second-line.regimens.

Ix. SUbSTITUTING WITHIN A FIRST-LINE ANTIRETROVIRAL DRUGREGImEN IN INFANTS AND CHILDREN bECAUSE OF DRUG TOxICITY


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Table . Severe toxicities in inants and children associated with specic rst-

line antiretroviral drugs and potential rst-line drug substitutions

First-lineARV drug

Most requent signicanttoxicity or the ARV drug

Suggested rst-line ARV drugsubstitution

ABC Hypersensitivity.reaction AZT

AZT Severe.anaemiaa.or.neutropeniab d4T.or.ABC

Lactic.acidosis ABCd.

Severe.gastrointestinal.intolerancec

d4T.or.ABCd4T Lactic.acidosis ABCd.

Peripheral.neuropathy AZT.or.ABCe

Pancreatitis

Lipoatrophy/metabolic.syndrome ABC.

EFV Persistent.and.severe.central.nervous.system.toxicity g

NVP

Potential.teratogenicity.(adolescent.girl.in.rst.trimester.o.pregnancy,.or.o.childbearing.potential.and.not.receiving.adequate.contraception)

NVP Acute.symptomatic.hepatitish EFV i

Hypersensitivity.reaction Preerred.substitution.o.NVP.to:.. a.third.NRTI.(disadvantage:.may.

be.less.potent). or

. PI.(disadvantage:.premature.start.o.class.usually.reserved.or.second-line)k

Severe.or.lie-threatening.rash.(Stevens-Johnson.syndrome) j

Note:.3TC/FTC-associated.pancreatitis.has.been.described.in.adults.but.is.considered.very.rare.in.children.a. Exclude.malaria.in.areas.o.stable.malaria,.severe.anaemia.is.dened.as.Hb.


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Poor.adherence,.inadequate.drug.levels,.prior.existing.drug.resistance.or.inadequate.potency.o.

the.drugs.chosen.can.all.contribute.to.ARV.treatment.ailure(83-86).Genetic.dierences.in.drug.metabolism.may.also.be.important.(92,.93).It.is.recommended.that.programmes.primarily.use.clinical.criteria,.supported,.where.possible,.with.CD4.criteria,.in.order.to.identiy.treatment.ailure.When. treatment. ailure. is. conrmed,. switching. to. a. new. second-line. regimen. becomes.necessary(i )

It.should.not.be.concluded,.on.the.basis.o.clinical.criteria,.that.an.ARV.regimen.is.ailing.until.the.child.in.question.has.had.a.reasonable.trial.on.the.therapy,.ie.the.child.should.have.received.the. regimen. or. at. least. 24. weeks,. adherence. to. therapy. should. have. been. assessed. and.considered.to.be.optimal,.and.any.intercurrent.opportunistic.inections.should.have.been.treated.

and.resolved,.and.immune.reconstitution.infammatory.syndrome.(IRIS).excluded.Additionally,.beore.considering.a.change.in.treatment.because.o.growth.ailure.it.should.be.ensured.that.the.child.is.receiving.adequate.nutrition.

Clinical denition o treatment ailure

The.detection.o.new.or.recurrent.clinical.events.classied.within.the.WHO.clinical.staging.may.also.refect.progression.o.disease.when.a.child.is.on.ART.Treatment.ailure.should.be.considered.when.either.new.or.recurrent.stage.3.or.4.clinical.events.develop.in.a.child.on.therapy.(Table.8)

Immune reconstitution infammatory syndrome

Clinical.disease.progression.should.be.dierentiated.rom.the.IRIS,.an.entity.that.has.been.observed.in.adults.and.less.requently.in.children.starting.ART,.particularly.those.with.very.low.CD4.values.(97-102).Symptoms.are.similar.to.those.seen.in.opportunistic.inections.They.usually.occur.within.the.rst.three.months.ater.the.start.o.potent.ART.(103),.concurrent.with.a.rapid.rise.in.CD4.values.It.is.also.possible.that.immunological.reconstitution.may.lead.to.the.development.o.atypical.presentations.o.some.opportunistic.inections.

(i). Switching.a.regimen.or.a.ailure.should.not.be.conused.with.substitution.o.a.single.drug.or.toxicity.(see.Section.IX)

x. SWITCHING AN ARV REGImEN IN INFANTS AND CHILDREN:TREATmENT FAILURE


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Table 8. Using the WHO Paediatric Clinical Staging to guide decision-making

on switching to second-line therapy or treatment ailure

New or recurrentevent on ART a, b

Management options c, d

[A (IV)]

No.new.events.or.PGL..(T1).

. Do.not.switch.to.new.regimen. Maintain.regular.ollow.up.

Stage.2.events

(T2)

. Treat.and.manage.staging.event. Do.not.switch.to.new.regimen

. Assess.and.oer.adherence.support.. Assess.nutritional.status.and.oer.support.. Schedule.earlier.visit.or.clinical.review.and.consider.CD4

Stage.3.events

(T3)

. Treat.and.manage.staging.event.and.monitor.responsee

. Check.i.on.treatment.24.weeks.or.more.. Assess.and.oer.adherence.support.. Assess.nutritional.status.and.oer.support.. Check.CD4...where.available.. Institute.more.requent.ollow-up

. Consider.switching.regimen.

Anti Retroviral Therapy guidelines

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