e1326
KEY WORDS
neurodevelopment, HIV, childhood development, antiretroviral
therapy, HAART
ABBREVIATIONS
ARVantiretroviral drug
HAARThighly active antiretroviral therapy
Dr Le Doar prepared and undertook the literature review and
was responsible for writing the rst draft of this article.
Professor Newell and Dr Bland reviewed the data and provided
comments during writing, and substantially contributed to, and
approved, the nal manuscript.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0405
doi:10.1542/peds.2012-0405
Accepted for publication Jun 26, 2012
Address correspondence to: Kirsty Le Doar, MBBS, MRCPCH, c/o
Paediatric Department, Croydon University Hospital, London
Road, Croydon CR7 7YE, UK. E-mail: kirstyledoare@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING: The Africa Centre for Health and Population Studies is
funded by a core grant from the Wellcome Trust (grant number
082384/Z/07/Z).
LE DOAR et al
REVIEW ARTICLE
METHODS
We searched the online databases
Medline, Embase, PsychINFO, Web of
Science, and PubMed for studies published in English between 1990 and
March 1, 2011, with the following search
terms: infant, child, HIV, neurodevelopment, cognitive impairment,
motor impairment, language impairment, antiretroviral therapy. The
search identied 210 studies in Medline; subsequent searches identied
additional studies: 16 in Embase, 7 in
PsychINFO, and 12 in PubMed. The
results of this review have been
reported using the checklist described
for writing systematic reviews by Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA).43
The current focus of HIV programs
globally is on prevention of mother-tochild transmission and early detection
of childhood infection with immediate
treatment. Therefore, to determine the
effect on neurodevelopment of maternal
e1327
CHARACTERISTICS OF STUDIES
Three-quarters of the studies reviewed
(75%) emanated from the United States
or Canada (n = 18)4461 and Europe
(n = 5),6266 whereas studies from
resource-poor settings accounted for
25%: Africa (n = 6),6772 South/Central
America and the Caribbean (n = 1),73
and Asia (n = 1).74 The characteristics
of the studies included in this review
are outlined in Tables 1, 2, and 3.
e1328
FIGURE 1
LE DOAR et al
1996
1999
1999
Culnane (48)
Raskino (49)
1995
Chase (46)
Pollack (44)
1994
Year
Nozyce (45)
First Author
(Reference
No.)
US
US and
France
US
US
US
Location
Cohort
Cohort
Cohort
Cohort
Cohort
Study
Type
831
332
91
51
274
All HIV-infected
HIV-exposeduninfected
HIV-unexposed = 27
HIV-infected = 22
HIV-exposeduninfected = 42
HIV-infected = 24
HIV-exposeduninfected = 27
All HIV-infected
Groups
Studied
2 mo18 y
03 y
0-2 y
470 mo
324 mo
Age at
Entry
TABLE 1 Infants Exposed to HIV/ARVS In Utero and Early Life in Resource-Rich Settings
BSID, MSCA,
WIT
BSID
MSCA
BSID
BSID
BSID
Development
Scale
Not antenatally.
On therapy depending
on disease stage.
ARVs not stated.
Exposure to ARVs
Growth, immunologic
parameters, birth
weight and gestation
Growth failure
Mean MDI and PDI
predictive of
scores comparable
neurocognitive
at birth but declined
scores.
versus controls by 12
mo if HIV-infected
(83.5 vs 112 vs 116,
P = .01). HIV-infected
10.5 times more
likely to have mean
MDI score .1 SD
lower and 4.4 times
more likely PDI mean
score ,85 (,1 SD)
below population
mean.
Not stated
Not stated
Additional
Outcome
Measures
Not stated
Early motor delay and
mental decline if HIVinfected versus HIVexposed-uninfected.
Mean scores
decelerate over time.
Variable outcomes,
even if HIV-infected.
Not stated
Developmental
Outcomes
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
REVIEW ARTICLE
e1329
e1330
LE DOAR et al
Smith (50)
Chase (47)
First Author
(Reference
No.)
2000
2000
Year
TABLE 1 Continued
US
US
Location
Cohort
Cohort
Study
Type
114
595
All HIV-infected
HIV-infected = 114
HIV-exposeduninfected = 481
Groups
Studied
03 y
036 mo
Age at
Entry
BSID
BSID
Development
Scale
Exposure to ARVs
Yes 48%
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Additional
Outcome
Measures
Prematurity,
At 4 mo no signicant
birth weighta
difference except in
mean scores. Mean
score ,1 SD from
the population mean
by 24 mo for both MDI
and PDI, P = .05. Early
HIV-1 infection was
associated with
a decline in
estimated mean
motor scores of 1
standard score point
per mo compared
with 0.28 point in the
late infected group (P
, .02). Estimated
mean mental scores
of the early-infected
group declined 0.72
point/mo, whereas
the average decline
of the late-infected
group was 0.30
point/mo (P , .13).
Developmental
Outcomes
2003
2006
Foster (64)
UK
US
Canada
Llorente (52)
Location
Year
First Author
(Reference
No.)
TABLE 1 Continued
Cohort
Cohort
Crosssectional
Study
Type
62
157
50
HIV-infected
HIV-infected = 25
HIV-exposeduninfected = 25
Groups
Studied
733 mo
036 mo
637 mo
Age at
Entry
BSID, GMDI
BSID
BSID
Development
Scale
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Not stated
38% to 63%
Exposure to ARVs
Additional
Outcome
Measures
Disease stage,
Lower verbal scores
worse stage = lower
than population
scores
mean. Children with
worse disease stage
have scores .2 SDs
below the population
mean, not improved
by HAART.
Developmental
Outcomes
REVIEW ARTICLE
e1331
e1332
LE DOAR et al
2010
Williams (53)
US
Italy
US
US
Location
Cohort
Crosssectional
Cohort
Crosssectional
Study
Type
HIV-exposeduninfected = 39
HIV-unexposed = 24
Groups
Studied
HIV-infected = 15
HIV-exposeduninfected = 14
29
63
02 y
2 wk36 mo
02 y
1836 mo
Age at
Entry
BSID
DDST
BSID
BSID
Development
Scale
Excluded
Yes -17%
11% to 25%
HIV-exposeduninfected
versus 12% HIVunexposed
Yes 51%
Additional In
Utero Exposure
to Drugs (Cocaine,
Heroin, Other)
Exposure to ARVs
Prematurity, low
birth weight
Additional
Outcome
Measures
Not stated
HIV-infected infants
62.5% abnormal
scores vs 14% if HIVexposed-uninfected.
Treatment before 12
wk of age improved
scores versus those
treated later.
Developmental
Outcomes
BSID, Bayley Scales of Infant Development; CI, condence interval; MDI, Mental Developmental Index; MSCA, McCarthy Scale of Childhood Abilities; PDI, Psychomotor Developmental Index; PI, protease inhibitor; RR, relative risk; WIT, Wechsler Intelligence Tests.
a Children followed until 5 y of age.
2008
2007
Lindsey (55)
Caplo (63)
2006
Year
Alimenti (54)
First Author
(Reference
No.)
TABLE 1 Continued
2000
2001
Blanchette (61)
2000
Bisiacchi (62)
Fishkin (57)
1992
Year
Levenson (56)
First Author
(Reference No.)
Canada
US
Italy
US
Location
80
42
49
Cross- sectional 25
Cross-sectional
Cross-sectional
Cross-sectional
Study Type
Groups Studied
HIV-infected = 14
HIV-exposeduninfected = 11
HIV-infected = 40
HIV-unexposed = 40
HIV-infected = 29
HIV-exposeduninfected = 13
HIV-infected = 41
HIV-exposeduninfected = 8
512 y
Mean 9.4 y
35 y
615 y
School-age
Age at Entry
WIT
WIT
Own tests
MSCA
Development Scale
Developmental
Outcomes
Additional Outcome
Measures
Not stated
Not stated
Executive function
scores lower in
HIV-infected than
HIV-exposeduninfected;
language and
memory scores
only poorer with
worse disease.
HIV-exposed
scores normal
for age.
Yes, not stated how All neurocognitive
many
scores lower in
HIV-infected
group but not
signicant, only
signicant
difference
executive
function: block
design 6.08 vs
7.53 P = .002
Not stated
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
CT changes
Not stated when.
Yes 20% in HIVNo differences in
4 children on ARVs +
associated with
infected mothers
cognition. Subtle
PI; 8 children
visuospatial and
ne and gross
ARVs without PI;
visuomotor
motor strength
Average no. of
difculties.
differences.
drugs = 2 (range
Signicant
04)
differences in
mean scores in
HIV-infected with
worse disease
stage.
Exposure to ARVs
REVIEW ARTICLE
e1333
e1334
LE DOAR et al
Smith (60)
Jeremy (59)
First Author
(Reference No.)
TABLE 2 Continued
2006
2005
Year
US
US
Location
Cohort
Cohort
Study Type
Groups Studied
HIV-exposeduninfected = 422
MSCA
WIT
37 y
BSID
Development Scale
24 mo 17 y
Age at Entry
Postnatally owing to
infection, not
stated if
antenatally.
Pre-1997:
zidovudine/
lamivudine (100),
stavudine
/ritonavir (97),
zidovudine/
lamivudine/
ritonavir (100).
Post-1997:
stavudine/
nevirapine/
ritonavir (41),
stavudine/
lamivudine/
nelnavir (63),
stavudine/
nevirapine/
nelnavir (44), or
the 4-drug (44)
Not stated if
antenatally.
Children treated
with:
35% monotherapy,
17% HAART, 10%
other multidrug
therapy but not
HAART.
Exposure to ARVs
Yes 41%
Additional Outcome
Measures
Developmental
Outcomes
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
Location
Study Type
2010
Thomaidis (66)
Greece
US
Cross-sectional
Cross-sectional
All HIV-infected
Groups Studied
60
HIV-infected = 20
HIV-unexposed = 40
HIV-exposeduninfected = 134
22
318 y
Mean age
11.76 y
916 y
9.46 y
Median
617 y
Age at Entry
WIT
GMDI
PPVT;WRAT III
SON
Development Scale
All HIV-infected
treated with
HAART not stated
when treatment
started. Not
stated if
antenatal
Not stated if
antenatal
exposure.
84% of youths on
ARVS not stated
which.
18 postnatally
treated with
HAART.
Not stated
antenatally
Exposure to ARVs
Additional Outcome
Measures
33% HIV-infected
Youths on ARVS had
scored below
lower WRAT III
10th centile in
scores than those
both tests.
not taking
medication
PPVT:HIV-infected
mean score 83.9
vs 85.3;
HIV-exposeduninfected: mean
score 87.5
HIV-infected with CT Prematurity and low
birth weight
changes had
lower mean
general, practical
and IQ scores P ,
.001. HIV-infected
without CT
abnormalities had
normal cognitive
scores but
increased
emotional
symptoms and
hyperactivity P ,
.05.
Not stated
Developmental
Outcomes
Not stated
Not stated
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
BSID, Bayley Scales of Infant Development; CI, condence interval; CT, computed tomography; GMDI, Grifths Mental Developmental Index; MDI, Mental Developmental Index; MSCA, McCarthy Scale of Childhood Abilities; PI, protease inhibitor; PPVT, Peabody
Picture Vocabulary Test; SON, Snijers-Oomen Non-verbal WIT; Wechsler Intelligence Tests; WRAT, Wide-Ranging Ability Test.
2009
Year
Brackis-Cott (58)
Koekkoek (65)
First Author
(Reference No.)
TABLE 2 Continued
REVIEW ARTICLE
e1335
e1336
LE DOAR et al
2008
2008
Leartvanangkui
(74)
2008
Smith (71)
1995
Year
Gay (73)
Author
Thailand
2008
2008
Congo
South
Africa
Haiti
Location
Groups Studied
39
HIV-infected
126 HIV-infected = 28
HIV-exposeduninfected = 98
Cross304 HIV-infected = 25
sectional
HIV-exposeduninfected = 279
HIV-exposeduninfected = 35
HIV-unexposed=90
Cross160 HIV-infected = 35
sectional
Cohort
Cohort
Study Type
05 y
Mean age
43.7 mo
1872 mo
Mean age
60 mo
024 mo
Age at Entry
DDST
BSID, PPVT,
SON
GMDI
BSID
Development
Scale
Additional Outcome
Measures
No
No
Developmental
Outcomes
No
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
Not in utero, 13
infants treated
with zidovudine,
mean age at
initiation 14.6 mo
Exposure to ARVs
2011 Zimbabwe
2010
Kandawasvika
(68)
HIV-exposeduninfected = 35
HIV-infected = 51
Groups Studied
Cohort
Cohort
593 HIV-infected = 16
HIV-exposeduninfected = 577
Cross115 HIV-infected = 92
sectional
HIV-exposeduninfected = 28
HIV-unexposed = 34
Cross86
sectional
Study Type
GMDI
BSID
BINS
,12 mo
BSID
Development
Scale
1015 mo
133 mo
Age at Entry
Not stated if
antenatally. 18
children
receiving HAART
66.6% of children on
ARVs at
recruitment
39.2% antenatally.
Exposure to ARVs
No
No
No
No
Additional In Utero
Exposure to Drugs
(Cocaine, Heroin,
Other)
Not stated
Additional Outcome
Measures
Head
circumference
and low birth
weight
associated with
low BINS scores
Stunting and
wasting common
and associated
with poorer
developmental
scores.
Scores reported as
a percentages:
66.6% HIV-infected had motor
delay versus 5.7% for
controls.
Children exposed to ARVs in
utero had fewer scores .2
SDs below the population
mean than those unexposed
to ARVs in utero.
Developmental
Outcomes
BINS, Bayley Infant Developmental Screener; BSID, Bayley Scales of Infant Development; DDST, Denver Developmental Screening Tool; GMDI, Grifths Mental Developmental Index; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; PI,
protease inhibitor; PPVT, Peabody Picture Vocabulary Test; SON, Snijers-Oomen Non-verbal.
2009 South
Africa
2001
Potterton (70)
South
Africa
2008
2009 South
Africa
2009
2009
Ferguson (67)
Location
Laughton (69)
Year
Author
TABLE 3 Continued
REVIEW ARTICLE
e1337
LONG-SURVIVING HIV-INFECTED
CHILDREN TREATED WITH ARVS IN
RESOURCE-RICH SETTINGS
Early studies of ARV-naive HIV-infected
children .30 months of age at study
enrollment demonstrated slower disease progression and better clinical
outcomes than infants who seemed to
have a more rapidly progressive disease and died early.20,76 These studies
did not collect data on maternal ARV
treatment in pregnancy and describe
characteristics of children who had
never been treated with ARVs.
In the earliest studies of children aged 3
to 18 years treated with dual therapy,
LE DOAR et al
REVIEW ARTICLE
HIV-EXPOSED-UNINFECTED
CHILDREN IN RESOURCE-RICH
SETTINGS
Few studies have evaluated the effects
of perinatal exposure to HIVand ARVs on
the neurodevelopment of children
who are HIV-exposed-uninfected. Interpretation of these results was difcult because of the heterogeneity of the
DEVELOPMENTAL OUTCOMES IN
HIV-INFECTED CHILDREN IN
RESOURCE-POOR SETTINGS
The association between HIV infection
and neurodevelopmental impairment
in infants and children in resource-poor
settings is not well described. In contrast to resource-rich settings, where
prevention of mother-to-child- transmission programs are widespread and
infants are predominantly formula fed,
children in resource-poor settings are,
until very recently, less likely to have
been exposed to ARVs in utero and early
life and are still predominantly
breastfed. In ARV-naive children, neurodevelopmental decits were reported in 6% to 40% of HIV-infected children
in resource-poor settings, depending
on disease stage.79,80
CONCLUSIONS
All studies identied HIV-infected
infants as having worse mean neurodevelopmental scores than the reference population in infancy with mean
scores consistently more than 1 SD
below the population mean, irrespective of whether they had been exposed to ARVs in utero or not. Infants
presenting with HIV infection before the
age of 3 months had the lowest scores.
Since the advent of prevention of
LE DOAR et al
mother-to-child-transmission
interventions, studies have indicated variable
improvement in mean developmental
scores in HIV-infected infants exposed
to a protease inhibitorbased HAART
regimen in utero. Infants commencing
treatment before the age of 12 weeks
demonstrated better, but still subnormal, mean locomotor scores, than
those with delayed treatment. No studies have yet examined the effect of early antiretroviral therapy on cognitive
scores.
Older HIV-infected children demonstrated near normal global neurocognitive scores, probably as a result of
slower disease progression in this
group. However, there is evidence that
subtle decits in higher cognitive
functioning (poorer memory, language
development) and behavior exist in
school-aged children with only limited
improvement after initiation of antiretroviral therapy. Evidence suggests
that the subtle differences detected in
older children in the pre-HAART era may
be improved with more effective HAART
and that language skills may be improved with a protease inhibitorbased
ARV regimen.
The evolution of more effective antiretroviral therapy, from single therapy
to HAART, appears to have had a positive
impact on mean neurodevelopmental
scores in infants and children in the
United States and Europe who are HIVinfected and HIV-exposed-uninfected.
Lately, results appear to highlight improved outcomes for children treated
with ARVs while they are still clinically
well. There is also an indication that
commencing HAARTat an earlier stage of
disease benets long-surviving children.
This highlights the importance of the
continuing effort to roll out the World
Health Organization recommendations42
in resource-poor settings for early and
more effective antiretroviral therapy to
all eligible pregnant women and their
infants.
REVIEW ARTICLE
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LE DOAR et al
References
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