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Optimization of antiretroviral therapy in HIV-infectedchildren under 3 years of age: a systematic review

Martina Penazzatoa,b,M, Andrew J. Prendergasta,c,d,M, Lulu M. Muheb,

Denis Tindyebwae and Elaine J. Abramsf

Background: Treatment of young HIV-infected children is challenging because of rapiddisease progression, high viral loads and few drug options. This review was undertakento update evidence on the management of young HIV-infected children and to informthe development of the 2013 WHO guidelines for antiretroviral therapy (ART) in lowand mid

Design:

(aged 100043.94, Pbased reimmunocontinuobecause

ConclusLopinavchildrenlopinaviload testreatmenevidencmend thbe subst

Keywor

aMRC Clinical Trials Unit a entre forPaediatrics, Blizard Institut HealthResearch, Harare, Zimbabw nda, andfICAP, M d Surgeons, Columbia University, Columbia, New York,USA.

CorrespoSwitzerla

E-mail: pMartina

DOI:10.ndence to Martina Penazzato, HIV Department, World Health Organization, 20 Avenue Appia, Geneva 1211,nd.

enazzatom@who.int

Penazzato and Andrew J. Prendergast contributed equally to the development of this manuscript.

1097/QAD.0000000000000240

ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins S137ailman School of Public Health and College of Physicians anight Lippincd treatment strategies in perinatally HIV-infected infants and young children3 years).

Eight studies were included. Antiretroviral therapy (ART) initiation in asympto-fants led to 74% reduction in mortality or disease progression [hazard ratio 0.36,fidence interval (CI) 0.180.74, P0.0002]. Regardless of previous exposure toon of mother to child transmission (PMTCT), treatment failure at 24 weeks wasely in children starting nevirapine-based than in those starting lopinavir/ritonavirir/r)-based ART (hazard ratio 1.79, 95%CI 1.332.41, P0.0001). Infants startingr/r-based ART and substituting lopinavir/r with nevirapine once virologic suppres-achievedwere less likely to experience viral loadmore than 50copies/ml (hazard2, 95%CI 0.410.92,P0.02) butmore likely to have confirmed virologic failurecopies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.360.002). Children receiving induction-maintenance ART (four-drug NNRTI-gimen for 36 weeks followed by three-drug ART) showed better short-termlogic and virologic responses, but no long-term benefits. The only trial comparingus ART from infancy with interrupted ART beyond infancy was terminated earlythe duration of treatment interruption was less than 3 months in most infants.

ion: ART initiation in asymptomatic infants reduces morbidity and mortality.ir/r-based first-line ART is superior to nevirapine-based regimens in young, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substitutingr/r with nevirapine following virologic suppression may be feasible where viralting is available. Considering current evidence, induction-maintenance andt interruption strategies are not recommended. This review contributed to thee base for the 2013 WHO guidelines on antiretroviral therapy, which recom-at all children below 3 years start lopinavir/r-based ART and that lopinavir/r canituted with nevirapine once sustained virologic suppression is achieved.

2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2014, 28 (Suppl 2):S137S146

ds: antiretroviral therapy, children, HIV infection, infants, randomizedcontrolled trial, systematic review

t UCL, London, UK, bHIV Department, World Health Organization, Geneva, Switzerland, cCe, Queen Mary University of London, London, UK, dZvitambo Institute for Maternal Childe, eAfrican Network for the Care of Children Affected by HIV/AIDS (ANECCA), Kampala, Ugaevaluate

Methods: We identified and critically assessed randomized controlled trials thatdle-income countries.

A systematic review and meta-analysis.ott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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Background

In the absence of antiretroviral therapy (ART), over50% ofdeath bydramaticchildreneligible(LMICs

There hrecommrecognizto reducto maxiimmunoART m(

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for analysis and pooling. When data on only one trialwere available for a question, individual trial results weredescribed.

The oriand wasrelevantlanguagHIV/AILibrary,Registethe follohttp://lchild, pART, deferred ART, HIV infection, HIV, acquiredimmunodeficiency syndrome, NNRTIs, NRTI, proteaseinhibitor, protease inhibitors, randomized controlledtrial anWorld Aconferentunisticfor unpclinicalorganiza

Two aurecordsif theyindepenwith anyauthorthe studpublicatusing th

Wherequestionrisks (Ranalysisfixed-ef(REM)If heteroby subgconduct

Result

In the uthe 735four addreviewin confeA total ocomparnot repoage we

children enrolled in the studies were not ART-naiveor definitions of the interventions being evaluatedsignificantly differed from the ones the review intended

exammar

k ofuenctrallyadequately concealed using opaque envelopes ortronic interfaces, opened at the time of randomizationll studies. Participants were not blinded to treatmentcatiocted

was onlythe remon labo

ctedrtednt-te exper], ARis unow-u

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ART in HIV-infected children under 3 years of age Penazzato et al. S139d controlled clinical trial. Abstracts from theIDS Conference, International AIDS Societyce and Conference on Retroviruses and Oppor-Infections were also screened. We searchedublished and ongoing studies using prospectivetrial registries, and by contacting researchtions and experts in the field.

thors (M.P. and A.J.P.) independently screenedidentified by the search. Studies were identifiedmet the eligibility criteria. M.P. and A.J.P.dently extracted, cross-checked and assessed data,disagreement resolved by consensus with a third(E.J.A.). If insufficient data were available iny report, further information was sought from theion authors. Methodological quality was assessede Cochrane risk of bias tool [16].

more than one trial was identified for thes being addressed, the hazard ratios or relativeRs) for each outcome were combined in a meta-to give a pooled hazard ratio or RR, using thefects model (FEM). A random-effects modelwas also used to test the robustness of the results.geneity was detected and could not be explainedroup analyses, then sensitivity analyses wereed.

s

pdated search, 881 records were identified; ofremaining after duplicates were removed,

itional studies were eligible for inclusion in this(Fig. 1). Four further records were identifiedrence proceedings, for a total of eight records.f 12 full text studies were excluded because directison with a control arm without intervention wasrted; infants or young children less than 3 years ofre not included or very poorly represented;

afferepointewerwas[20biasfoll

TheandsoVirall sas rstopfromtriainfaDSMbyrestspenabilPEHwasbetwassecomnevchilwhi

Eff

WhTwohazindginal search was conducted on 1 November 2010updated on 1 August 2012.We sought to identifystudies from 1997 to the search date, regardless ofe or publication status, by searching the CochraneDS Review Group Trials Register, CochranePubMed, EMBASE and the Cochrane Centralr of Controlled Trials (CENTRAL). In addition,wing specific search terms supplementary data,inks.lww.com/QAD/A496 were used: infant,(a)ediatric, HAART, antiretroviral agents, early

tosum

RisSeqcenwaselecin aalloaffeight Lippincott Williams & Wilkins. Unauthorizen, but the study endpoints were unlikely to beby unmasking. Blinding of outcome assessmentreported for the CHER trial [17]; however, for

aining studies, endpoint assessments relied mainlyratory measurements, which are unlikely to beby unmasking. Incomplete outcome data werefor NEVEREST [18], wherein a modified

o-treat analysis was conducted, but few patientscluded. An intent-to-treat analysis of all patientsformed for CHER, P1060 cohorts 1 [19] and 2ROW [21] and OPH-03 [22], such that attritionlikely to significantly affect the results. No loss top was reported for PEHSS [25].

mary outcome was prespecified in study protocolsvided in study reports or by the investigators,tive reporting of this outcome is unlikely.ic and immunologic outcomes were reported ines. P1060 cohorts 1 and 2 were terminated early,mended by the DSMB; despite prespecifiedcriteria being applied, potential biases arising

ly termination should be considered. The CHERmodified to recall and evaluate all deferred armor initiation of immediate ARTon advice of theSimilarly, early termination was recommendedDSMB in OPH-03 due to the high rate ofg ART in the interruption arm; the short timeff ART in the this arm may have reduced theo detect differences in growth between groups.was originally designed as a feasibility study andt powered to assess differences in mortalityarms. Similarly, PROMOTE was designed to

alaria outcomes and was therefore not powered tovirologic responses between lopinavir/r and

ne-based regimens. NEVEREST randomizedwho had already achieved virologic suppression,ay limit its generalizability.

of interventions

to startdies assessed when to start treatment. The pooledatio for time to death of 0.36 (95% CI 0.180.74)s a 64% relative reduction in mortality amongine. Characteristics of included studies areized in Table 1 [1724].

bias in included studiese generation was computerized and performedby the trial statistician in all studies. Allocationd reproduction of this article is prohibited.

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infantswith thimmunooutcomassessedage instatus w0.25, 95or diseament. Hthe cotreatmeninfancy.a meta-endpoin

What tThree stin childrpoweredindepen

S140 AIDS 2014, Vol 28 (Suppl 2)

First search (November 2010):1921 records identified

through database searching

Update (August 2012):881 records identified

through database searching

4 additionalrecords

identified

ds afremo

ordsned

-textsess

ibility

iesd intivesis

Fig. 1. P1308 records afterduplicates removed

735 recorduplicates

50 recordsscreened

41 recordsexcluded

49 recscree

9 full-textarticles

assessed foreligibility

5 full-textarticles

excludedwith reasons

12 fullarticles as

for elig

4 studiesincluded inqualitativesynthesis

3 studincludequalitasynthet Lippincott Williams & Wilkins. Unauthorized r

starting early lopinavir/r-based ART comparedose starting deferred ART once clinical orlogic criteria were met (Table 2). The combinede of mortality or disease progression could only befor CHER. Treatment initiated at 612 weeks ofasymptomatic infants with good immunologicas associated with a 75% reduction (hazard ratio%CI 0.120.51, P 0.0002) in time to mortalityse progression, compared with deferred treat-owever, no randomized trial data demonstratemparative efficacy of starting vs. deferringt in children who first present beyond earlyImmunologic response was not combined inanalysis, as the two studies provided differentts.

o startudies assessed what antiretroviral regimen to starten less than 3 years of age (Table 1). No study wasto assess mortality or disease progression as

dent endpoints. In meta-analysis, the hazard for

treatmendiscontiincludinhigherstartingconsiderwere cosimilarThere wa similarnevirapiResults

The haz1.292.than th0.0008)(or deatgroup wthose abwithin t

8 studies includequalitative analy

when to start (n lopinavir/ritonavir vs nevir

planned treatminterruption (n =

induction-maintanancsubstituting lopinavir

with nevirapine (n

RISMA flowchart of study selection process.fromrelevant

conferenceabstractbookster

ved

37 recordsexcluded

9 full-textarticles

excluded, withreasons

edeproduction of this article is prohibited.

t failure (a composite of virologic failure ornuation of the study drugs for any reason,g death) was 1.79 (95% CI 1.332.41) timesin children starting nevirapine than in thoselopinavir/r-based regimens (P< 0.0001). Whening only the two cohorts of P1060, the findingsnsistent across studies, indicating that results arefor NNRTI-exposed and -unexposed children.as no clear difference in effect by age group, withrisk of treatment failure among children startingne-based regimens above or below 12 months.were similar when an REM was used (Table 2).

ard for virologic failure was overall 1.84 (95% CI63) times higher for children starting nevirapineose starting lopinavir/r-based regimens (P(Fig. 2). The hazard ratio for virological failureh) in the nevirapine compared with lopinavir/ras greater in children below 12 months, than inove 12 months, with no differences between trialshese age groups (Fig. 3).

d insis

= 2),apine (n = 3),ent 1),e (n = 1),/ritonavir = 1)

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

ART in HIV-infected children under 3 years of age Penazzato et al. S141

Table

1.Summaryofcharacteristicsofincluded

studies.

Trial

Country

Question

Participants

Trial

details

CHER

[17]

South

Africa

When

should

antiretroviral

therapybestartedin

youngchildren?

377

Asymptomatic

HIV-infected

infantsaged

612weeks,withCD4cellcount2

5%,wererandomized

toim

mediate

ARTfor40weeks;im

mediate

ARTfor96weeks;deferredARTaccordingto

WHO

criteria.

First-lineARTregimen

comprisedzidovudine,

lamivudine,

lopinavir/r.Primaryoutcomes:timeto

death

orfailure

offirst-lineART(defined

asfailure

toreachCD4T-cellcount2

0%

byweek24ofART;

decreaseto

CD4cellcount24monthsandhad

CD4cellcount>25%

andnorm

alized

growth.Infantswererandomized

tocontinue(n21)orinterrupt(n21)treatm

entat

amedian(IQR)ageof29(2934)and30(2935)

months,respectively.Theprimaryendpointswereweight-for-heightZ-scores(W

HZ)andseriousadverse

events.

ART,antiretroviraltherapy;

IQR,interquartile

range;SA

Es,seriousadverseevents.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S142 AIDS 2014, Vol 28 (Suppl 2)

Study or subgroupP1060 cohort 1P1060 cohort 2PROMOTE-Peds

1.14440.6931

0.3425

0.3990.232

0.4395

20.9%61.9%17.2%

3.14 [1.44, 6.86]2.00 [1.27, 3.15]0.71 [0.30., 1.68]

100.0%Total (95% CI)Heterogeneity: CHi2 = 6.62, df = 2 (P = 0.04): I2 = 70%Test for overall effect: Z = 3.34 (P = 0.0008)

1.84 [1.29, 2.63]

0.1 0.2 0.5 1 2 5 10

log [Hazard ratio] SE WeightHazard ratio

IV, fixed, 95% CIHazard ratio

IV, fixed, 95% CI

Lopinavir/ritonavir Nevirapine

Fig. 2. Forest plot of virologic failure or death: nevirapine-based vs. lopinavir/r-based first-line antiretroviral therapy.

Table 2. Summary of results.

Outcome or subgroup Studies Participants Statistical method Effect estimate

Early vs. deferred antiretroviral treatmentMortality 2 (17, 24) 440 Hazard ratio (IV, Fixed, 95% CI) 0.36 [0.18, 0.74]Mortality or disease progression 1 (17) 377 Hazard ratio (IV, Fixed, 95% CI) 0.25 [0.12, 0.51]

Nevirapine-based vs. lopinavir/r-based first-lineantiretroviral therapy

Treatment failure (virologic failure or treatmentdiscontinuation)

3 (19, 20, 23) 583 Hazard ratio (IV, Fixed, 95% CI) 1.79 [1.33, 2.41]

Treatment failure (virologic failure or treatmentdiscontinuation)

2 (19, 20) 452 Hazard ratio (IV, Fixed, 95% CI) 2.01 [1.47, 2.77]

Infants (less than 12 months old) 2 (19, 20) 200 Hazard ratio (IV, Fixed, 95% CI) 2.03 [1.24, 3.32]Children (older than 12 months) 2 (19, 20) 251 Hazard ratio (IV, Fixed, 95% CI) 2.00 [1.32, 3.03]

Virological failure or death 3 (19, 20, 23) 583 Hazard ratio (IV, Fixed, 95% CI) 1.84 [1.29, 2.63]Virological failure or death 2 (19, 20) 452 Hazard ratio (IV, Fixed, 95% CI) 2.28 [1.55, 3.34]Infants (less than 12 months) 2 (19, 20) 200 Hazard ratio (IV, Fixed, 95% CI) 3.88 [2.06, 7.30]Children (older than 12 months) 2 (19, 20) 251 Hazard ratio (IV, Fixed, 95% CI) 1.67 [1.03, 2.70]

Change in CD4R T-cell count% from baseline 3 (19, 20, 23) 356 Mean difference (IV, Fixed, 95% CI) 1.18 [S0.50, 2.86]Change in weight z-score from baseline 3 (19, 20, 23) 360 Mean difference (IV, Random, 95% CI) 0.19 [S0.23, 0.61]Change in height z-score from baseline 3 (19, 20, 23) 374 Mean difference (IV, Fixed, 95% CI) 0.16 [S0.01, 0.32]Adverse events 3 (19, 20, 23) 506 Risk ratio (M-H, Fixed, 95% CI) 1.21 [0.88, 1.65]

Switch to nevirapine vs. continue on lopinavir/rVirologic failure (any VL >50 copies/ml) 1 (18) Hazard ratio (IV, Fixed, 95% CI) 0.62 [0.41, 0.92]Virologic failure (confirmed VL >1000 copies/ml) 1 (18) Hazard ratio (IV, Fixed, 95% CI) 10.19 [2.36, 43.94]Decline by 10% in CD4R T-cell count% at week 52 1 (18) 195 Risk ratio (M-H, Fixed, 95% CI) 0.22 [0.07, 0.74]Decline by 1 z-score in weight-for-age at week 52 1 (18) 195 Risk ratio (M-H, Fixed, 95% CI) 0.32 [0.11, 0.94]ALT increase (Grade 3/4) 1 (18) 195 Risk ratio (M-H, Fixed, 95% CI) 1.80 [0.55, 5.97]Neutropenia (grade 3/4) 1 (18) 195 Risk ratio (M-H, Fixed, 95% CI) 1.72 [0.42, 6.99]

Induction-maintenance strategyIncrease in CD4R T-cell count% from

baseline at week 361 (21) 228 Mean difference (IV, Fixed, 95% CI) 2.90 [0.80, 5.00]

Increase in CD4R T-cell count % frombaseline at week 72

1 (21) 225 Mean difference (IV, Fixed, 95% CI) 0.60 [S1.56, 2.76]

Increase in CD4R T-cell count % frombaseline at week 144

1 (21) 228 Mean difference (IV, Fixed, 95% CI) 0.50 [S1.70, 2.70]

Virologic response (VL

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There was weak evidence of greater increases in CD4%,weight-for-age Z-scores and height-for-age Z-scores inthe nevirapine compared with lopinavir/r arms. Adverseevents associated with treatment were similar betweengroups (Table 2).

Substituting lopinavir/ritonavir with nevirapineOne trial, NEVEREST [18], addressed the question oflopinavir/r substitution. Children substituting nevirapinefor lopinavir/r had a lower risk of having at least oneviral load greater than 50 copies/ml but a higher riskof confirmed virologic failure (>1000 copies/ml), thanthose remaining on lopinavir/r. CD4% increase was lowerin the lopinavir/r than in the nevirapine group. Weight-for-age Z-scores were similar on average, but fewerchildren in the nevirapine group experienced a decline inweight-for-age. Grade 3 or 4 elevations in ALT weremore common in the nevirapine group, but events wererare and no association was found with study arm.Similarly, grade 3 or 4 neutropenia was rare and similaracross arms (Table 2).

Induction-maintenanceOne trimaintenthe subsThere wmean C(Table 2CD4%drug, archildrenthree-drmaintainbetweengrowth

Planned treatment interruptionAlthough three trials investigated planned treatmentinterruptions, only one, OPH-03 [22], was designedto directly compare continuous ART from infancy vs.interruption. Growth and SAEs were similar betweenarms (Table 2); however, the trial was stopped earlybecause 14 out of 21 (67%) children in the interruptionarm had to restart ARTwithin 3 months.

Discussion

Paediatric HIV remains an important public healthproblem, with an estimated 700 infants newly infectedeach day [3]. Historically, clinicians have varied in theirpractice regarding when to start ART in young children.Furthermore, decisions around which ART regimen tostart are complicated by drug resistance in the context ofnevirapine exposure, few drug choices, uncertain dosingand long-term toxicities. However, as reviewed here,there are now trial data to inform treatment choices andmanagement strategies for infants and young children.

quthecedtores

ings,opeaiatioings,venonspronts

ART in HIV-infected children under 3 years of age Penazzato et al. S143

.85 [193 [1.48 [2.0

.86 [0

8 [1.55, 3.34]

.65 [0Not

7 [1.0

%

azarfixed,

Fig. 3. F rapintherapy.al, ARROW [21], investigated an induction-ance ART strategy; we report results foret of 370 (31%) children below 3 years of age.as no significant difference between groups inD4% change from baseline at 72 or 144 weeks); however, at 36 weeks, there was a greaterincrease in the four-drug, compared with three-ms. At 24 weeks, virologic response was better inreceiving four-drug than in those receiving

ug regimens; however, this effect was noted at 48 weeks. There were no differencesgroups in mortality, disease progression or

(Table 2).

ThebyreduizedThesettEurinitsettor edemEIDInfa

Study or subgroupInfants (less than 12 months)

Children (older than 12 months)

P 1060 cohort 1P 1060 cohort 2

1.3481.3656

0.40830.5259

22.8%13.8%

36.6%

7.3%56.1%

0.72280.2606

0

0.62050.5007

063.4%

33.

3.8

1

100.0% 2.2

1

1.6

Subtotal (95% CI)Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.98); I2 = 0%Test for overall effect: Z = 4.20 (P < 0.0001)

P 1060 cohort 1P 1060 cohort 2PROMOTE-PedsSubtotal (95% CI)Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 = 0%Test for overall effect: Z = 2.10 (P < 0.004)Total (95% CI)Heterogeneity: Chi2 = 4.34, df = 3 (P = 0.23); I2 = 31%

Test for subgroup differences: Chi2 = 4.31, df = 1 (P = 0.04); I2 = 76.8Test for overall effect: Z = 4.21 (P < 0.0001)

Log [Hazard ratio]H

IV, SE Weight

orest plot of age subanalysis for virologic failure or death: neviight Lippincott Williams & Wilkins. Unauthorize0.1 0.2 0.5 1Lopinavir/ritonavir Nevirapine

2 5 10

e-based vs. lopinavir/r-based first-line antiretroviralestion of when to start ART has been clarifiedCHER trial [17], which showed significantlymorbidity and mortality among infants random-immediate vs. deferred lopinavir/r-based ART.ults of CHER were felt to be relevant to allas reflected by changes in United States [26],n [27] and WHO guidelines [5] to recommendn of ART early in infancy. However, in manyearly infant diagnosis (EID) of HIV is delayedunavailable, and loss-to-follow-up is high [28],trating the importance of an effective PMTCT/gramme if infants are to benefit from early ART.in CHER started ART at 612 weeks of age;

.73, 8.57]0, 11.02]6, 7.30]

.45, 7.67]

.99, 2.75]estimable3, 2.70]

d ratio 95% CI

Hazard ratioIV, fixed, 95% CId reproduction of this article is prohibited.

Copyrigh

whether there would be additional benefit to very earlyinitiation of ART (close to birth), as has been hypo-thesized following report of a functional cure in anHIV-infunclear.settingscurrentltrial doechildrenguidelinbelowpaediatrCD4 cof ARTclinicalThe PR112 yecounts(once Crence inmodellithe InteAIDS-Simmediwith ARholds (guidelinstrategiewhereand follto recothresholinfancy.

The P10both neunexpowas arandomto a lopwas a fafailure oreason,combinany diff12 moconsiderendpoindifferenmay bedue to tnevirapi

It remato nevirto NNRexplanatance and

may be problematic in the context of high viralloads during infancy. It is possible that infants withoutdocumented NNRTI exposure were actually carrying

RTiesbabOMerenchilpoinherre ar neiremats,su

r ovelinall ilopinuldre pa

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S144 AIDS 2014, Vol 28 (Suppl 2)ected infant in the United States [29], remainsHowever, with an increased interest in someof moving EID closer to birth, studies arey underway to evaluate this strategy. The CHERs not resolve the issue of when to treat youngbeyond early infancy. Revised 2013 WHO

es [4] recommend ART initiation for all children5 years of age, with the goal of simplifyingic treatment (particularly in the absence ofell count testing) and facilitating rapid scale-upfor children in LMIC, but there are no

trial or cohort data to support this approach.EDICT trial, which randomized children agears (26% below 3 years of age) with CD4 T-cellof 1524% at enrolment, to early vs. deferredD4 T-cell count

Copyr

progression was rapid after ART interruption, with two-thirds of children restarting ARTwithin 3 months. TwoSouth African trials (PEHSS [24] and CHER [34]),whichdifferenfound tART anthan wwhere cART is

In summtreatmenguidelinuniversaof age, tfacilitatehave ledfor childr-based where feasible. Few high-burden countries arecurrently using first-line protease inhibitors in youngchildren; adopting these new recommendations willthereforprovisiorole of nyet to ban alternline regmaintenstrategieare neebenefitefavirenvirologiurgent nand ecoof bettterm toapproac

Ackno

An expthe CocparticulprovidedAvy Viothe NEVOPH03the PROWalker,Gibb, Moriginalindepengratefulfor thei

M.P. and A.J.P. were the lead authors. M.P. and A.J.P.scrutinized identified studies for eligibility, extracteddata and assessed the methodological quality of included

ies.ewe

nflicP. is aA. isls.

add

ne d

fere

NewDabHIV364

2. Gibcase201201menWorof aGenpubWorpregtowhealniza978Arpaet aHIVretrPicaKekrecotherPLoSPrenAbration9:e1ArriMasmotvert200Martinson NA, Morris L, Gray G, Moodley D, Pillay V, Cohen S,et al. Selection and persistence of viral resistance in HIV-infeJ AcChuMusincrwhoResLocetaldoseMusRespbaseto s25:9

ART in HIV-infected children under 3 years of age Penazzato et al. S145e require significant expansion of lopinavir/rn and development of better formulations. Theewer drug classes, such as integrase inhibitors, hase evaluated in young children, but could provideative to NNRTI or protease inhibitor based first-imens. Given the findings of the induction-ance and treatment interruption trials, theses are not currently recommended. Further dataded to determine which children would mostfrom substituting lopinavir/r with nevirapine orz and to evaluate the impact of this strategy onc control and treatment sequencing. There is aneed for further research into the programmaticnomic consequences of early ART; developmenter drug formulations; monitoring of long-xicities; and evaluation of alternative treatmenthes for infants and young children in LMICs.

wledgements

anded version of this review is published inhrane Database of Systematic Reviews. We arearly grateful to the following researchers whofor these analyses: Jane Lindsey, Paul Palumbo,lari and the P1060 trial team; Louise Kuhn andEREST trial team; Grace John-Stewart and thetrial team; Theodore Ruel, Jane Achan andMOTE-Peds trial team; Adrian Cook, Sarah

Diana Gibb and the ARROW trial team. Dianaark Cotton and Jayne Thierny contributed to theversion of this review and Steve Welch provideddent study review in the original version. We areto Amberle Durano, Tara Horvath and Joy Oliverr support in the search and update process.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.started treatment in healthier infants and hadt designs but a similar rationale to OPH-03, alsohat young children starting early, time-limitedd then interrupting needed to restart soonerould be feasible in a public health approach,lose follow-up and monitoring of children offchallenging.

ary, there is an unequivocal benefit to earlyt initiation in HIV-infected infants. WHO 2013es have extended the recommendation forl early ART to include all children below 5 yearso simplify paediatric treatment programmes andrapid scale-up. Findings from the P1060 trialsto a change in recommended first-line ART

ren below 3 years of age, which is now lopinavir/

studrevi

CoA.J.E.J.tria

No

No

Re

1.ight Lippincott Williams & Wilkins. Unauthorizected children after exposure to single-dose nevirapine.quir Immune Defic Syndr 2007; 44:148153.rch JD, Mwatha A, Bagenda D, Omer SB, Donnell D,oke P, et al. In utero HIV infection is associated with aneased risk of nevirapine resistance in ugandan infantswere exposed to perinatal single dose nevirapine. AIDSHum Retroviruses 2009; 25:673677.kmanS, ShapiroRL, SmeatonLM,WesterC, Thior I, Stevens L,.Response toantiretroviral therapyafter a single,peripartumof nevirapine. N Engl J Med 2007; 356:135147.iime V, Ssali F, Kayiwa J, NamalaW, Kizito H, Kityo C, et al.onse to nonnucleoside reverse transcriptase inhibitor-d therapy inHIV-infected childrenwith perinatal exposureingle-dose nevirapine. AIDS Res Hum Retroviruses 2009;89996.M.P. performed the analysis. All authors criticallyd the manuscript before submission.

ts of interestcoinvestigatoron thePEHSSandARROWtrials.a coinvestigator on the P1060 and NEVEREST

itional conflicts to declare.

eclared.

nces

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