Review

HIV-exposed, uninfected infants: new global challenges in

the era of paediatric HIV elimination
Ceri Evans, Christine E Jones, Andrew J Prendergast

The number of infants infected with HIV is declining with the rise in interventions for the elimination of paediatric Lancet Infect Dis 2016;
HIV infection, but the number of uninfected infants exposed to HIV through their HIV-infected mothers is 16: e92–107

increasing. Interest in the health outcomes of HIV-exposed, uninfected infants has grown in the past decade, with Published Online
March 31, 2016
several studies suggesting that these infants have increased mortality rates, increased infectious morbidity, and
http://dx.doi.org/10.1016/
impaired growth compared with HIV-unexposed infants. However, heterogeneous results might reflect the inherent S1473-3099(16)00055-4
challenges in studies of HIV-exposed, uninfected infants, which need large populations with appropriate, Blizard Institute, Queen Mary
contemporaneous comparison groups and repeated HIV testing throughout the period of breastfeeding. We review University of London, London,
the effects of HIV exposure on mortality, morbidity, and growth, discuss the immunological abnormalities identified UK (C Evans MBBCh,
A J Prendergast DPhil);
so far, and provide an overview of interventions that could be effective in this susceptible population. As the number
Zvitambo Institute for
of infants infected with HIV declines, the health needs of HIV-exposed, uninfected infants should be prioritised Maternal and Child Health
further, to ensure that post-2015 Sustainable Development Goals are achieved. Research, Harare, Zimbabwe
(C Evans, A J Prendergast);
Paediatric Infectious Diseases
Introduction few management options were available for HIV-infected
Research Group, Institute for
Mother-to-child transmission is one of the great tragedies infants at that time. However, despite many subsequent Infection and Immunity,
of the HIV epidemic, particularly in sub-Saharan Africa, studies, the precise effect of vertical HIV exposure on St George’s, University of
where 90% of new infections occur. Although the global child health remains unclear. Interpretation of published London, London, UK
(C E Jones PhD); and
target to eliminate paediatric HIV by 2015 has not been findings is complicated by several factors: (1) early studies
Department of International
achieved, there has been huge progress in the reduction of did not include HIV testing, making the effect of HIV Health, Johns Hopkins
the number of HIV-infected infants through expansion of exposure difficult to separate from infant HIV infection; Bloomberg School of Public
prevention of mother-to-child transmission (PMTCT) (2) follow-up testing of HIV-uninfected mothers and Health, Baltimore, MD, USA
(A J Prendergast)
programmes. In the pre-antiretroviral therapy (ART) era, infants to ensure accurate HIV status is often not available;
Correspondence to:
up to 40% of infants acquired HIV from their mothers,1 but (3) HIV-unexposed comparison groups have either not
Dr Andrew J Prendergast, Centre
with increasing availability of effective PMTCT been included, or are not demographically comparable; (4) for Genomics and Child Health,
interventions, transmission rates close to 1% are possible HIV-exposed, uninfected infants and HIV-unexposed Blizard Institute, Queen Mary
in breastfeeding populations in developing countries,2 and infants often differ in breastfeeding uptake and duration; University of London,
London E1 2AT, UK
less than 1% in non-breastfeeding populations.3 The and (5) the contributions of HIV and ART exposure are
a.prendergast@qmul.ac.uk
existing public health approach to PMTCT is initiation of not distinguishable in contemporary studies. Despite
lifelong ART for all pregnant and breastfeeding women these limitations, several large studies suggest that HIV-
(so-called Option B+)4 to eliminate new HIV infections in exposed, uninfected infants have increased mortality and
children and keep their mothers alive.5 As PMTCT coverage morbidity in early life.
expands, therefore, the number of HIV-infected infants is
declining, but the number of HIV-exposed, uninfected Mortality in the pre-ART era
infants is increasing (figure). As progress towards The largest HIV-exposed, uninfected cohort (ZVITAMBO),8
elimination of paediatric HIV infection accelerates, HIV- which prospectively followed up 14 110 infants in
exposed, uninfected infants are increasingly being Zimbabwe before availability of ART, found three times
recognised as a group potentially susceptible to uncertain higher mortality in HIV-exposed infants compared with
health needs. In this Review, we summarise the evidence of HIV-unexposed infants up to 2 years of follow-up; this
mortality, infectious morbidity, immune function, and mortality risk was higher in the first year of life compared
growth of HIV-exposed, uninfected infants, and highlight with the second (table 1). Infants and mothers had regular
research gaps that need to be addressed to better define HIV testing, and sensitivity analyses showed that higher
interventions for this growing population. mortality was not due to unascertained postnatal HIV
transmission.8 A study from Uganda10 reported signi-
Mortality and morbidity ficantly higher mortality among HIV-exposed, uninfected
The observation that infants exposed to HIV, but not infants at 18 months of age, but not at 12 or 24 months. A
infected, might have increased susceptibility to infections Zambian study,11 which prospectively assessed infants
first emerged in 1992 when HIV-exposed, uninfected from 9 months to 3 years of age, showed three times
infants in Kenya were found to have a high incidence of higher mortality in HIV-exposed, uninfected children
measles.6 In 1993, HIV-exposed, uninfected infants in compared with HIV-unexposed infants (95% CI 0·7–14·0).
Zaire were noted to have a greater risk of persistent Statistical power in these studies could have been limited
diarrhoea than HIV-unexposed infants;7 HIV-exposed, by small sample sizes. Studies with longer follow-up
uninfected infants were highlighted as a priority group, as periods report mixed results. HIV-exposed, uninfected

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 Review

600 000 exposed to PMTCT and receiving co-trimoxazole

1 600 000 prophylaxis, but breastfeeding duration was significantly
500 000 shorter than in HIV-unexposed infants.
Number of pregnant women living with

1 400 000
Studies comparing mortality in middle-income and

Number of new HIV infections in

1 200 000 high-income countries are scarce, but a need to
400 000
determine the impact of HIV exposure in these settings

children in LMICs
1 000 000
HIV in LMICs

300 000 exists, particularly in the current ART era.

800 000

600 000 200 000 All-cause morbidity and hospitalisation

62%
400 000 47%
56%
47%
31%
40%
100 000
200 000
13%
22%
0 0
2005 2006 2007 2008 2009 2010 2011 2012
Year
Figure: Reduction in perinatally HIV-infected infants with increasing PMTCT coverage
The number of pregnant women living with HIV in low-income and middle-income countries (white bars) declined
between 2005 and 2012, from 1·64 million to 1·48 million. In the same period, the proportion of HIV-infected
pregnant women receiving effective PMTCT interventions (green bars) increased substantially from 13% in 2005
to 62% in 2012, leading to a reduction in the number of HIV-infected infants (green line). The number of
HIV-exposed uninfected infants is, therefore, increasing. Data from WHO and UNAIDS. LMICs=low-income and
middle-income countries. PMTCT=prevention of mother-to-child transmission.
For the original data from WHO children in Rwanda had no increase in mortality up to
and UNAIDS see http://www. 5 years,12 but in The Gambia, uninfected children exposed
who.int/hiv/data/arvpmtct2014.
png and http://www.unaids.org/
to HIV-1 and HIV-2 who survived beyond 4 months of age
sites/default/files/media_asset/ had increased mortality up to a median age of 6 years
JC2571_AIDS_by_the_numbers_ compared with HIV-unexposed children.13
en_1.pdf
Mortality in the ART era
Where infants were exposed to one drug (single dose
nevirapine or zidovudine monotherapy) for PMTCT for a
short period of time, results have been heterogeneous.
Findings from a large South African study14 showed no
difference in 12-month mortality between HIV-exposed,
uninfected infants and unexposed groups. Most infants in
both groups were exclusively breastfed, which might have
partly mitigated differences. Results from a smaller South
African study,15 in which HIV-exposed, uninfected infants
were less likely than HIV-unexposed infants to breastfeed
beyond 12 weeks, showed no difference in mortality up to
36 weeks of age, although approximately one-third were
recruited from a wealthier area where formula feeding
might have been safe. Mortality was four times higher in
HIV-exposed, uninfected infants exposed to single dose
nevirapine and 6 months of zidovudine for PMTCT in the
Mashi trial16 in Botswana than in HIV-unexposed infants
up to 24 months of age. In a large trial in Malawi, Tanzania,
and Zambia,17 HIV-exposed, uninfected infants had 50%
higher 12-month mortality despite single dose nevirapine
and co-trimoxazole prophylaxis. Researchers of a small
study from Mozambique,18 in which HIV-exposed infants
received co-trimoxazole prophylaxis, single dose
nevirapine, and 4 weeks of zidovudine, found a trend
towards increased mortality in HIV-exposed, uninfected
infants (odds ratio [OR] 3·74, 95% CI 0·41–34·3). In a
small Ugandan study,19 mortality was almost 14 times higher
(13·7, 1·12–167·3) in HIV-exposed, uninfected infants
Before the availability of ART, HIV-exposed, uninfected
infants in the ZVITAMBO trial9 had more hospitalisations
during the neonatal period and more all-cause clinic visits
throughout infancy, compared with HIV-unexposed
infants, particularly for pneumonia and oral thrush. In the
ART era, investigators of a large South African study20
found no difference in late-onset sepsis, and a slightly
lower incidence of early-onset sepsis, in HIV-exposed,
uninfected infants during the neonatal period. However,
HIV-exposed, uninfected infants receiving single dose
nevirapine and 6 months of zidovudine for PMTCT in the
Mashi trial16 in Botswana were more than two times more
likely to be admitted into hospital than HIV-unexposed
infants up to 24 months. In infants surviving to 20 months
of age in Malawi, no differences in hospital admissions
were observed between HIV-exposed, uninfected infants
and HIV-unexposed infants, although this study might
have been limited by survival bias.21 Results from one
small study22 from South Africa showed that, whereas the
frequency of infections in HIV-exposed, uninfected
infants and HIV-unexposed infants was similar,
HIV-exposed, uninfected infants had a trend towards
more hospital admissions (relative risk [RR] 2·74, 95% CI
0·85–8·78). HIV-exposed, uninfected infants in
Mozambique receiving co-trimoxazole prophylaxis, single
dose nevirapine, and 4 weeks of zidovudine, had fewer
outpatient clinic attendances than HIV-unexposed infants
at 12 months, and similar hospitalisation rates.18
The most common infections in HIV-exposed,
uninfected infants in sub-Saharan Africa, Latin America,
and the Caribbean are skin infections, lower respiratory
tract infections, and oral thrush.9,23 Reports exist of
unusual infections in HIV-exposed, uninfected infants,
including invasive group A streptococcal disease,
haemorrhagic varicella, and oral and invasive candida.9,24,25
HIV-exposed, uninfected infants seem to have more
severe infections and a greater risk of treatment failure,
especially in pneumonia,22,24,26–28 and higher rates of
surgical complications.29
Pneumonia
Pneumonia was more common in HIV-exposed, uninfected
infants up to 6 months of age in Zimbabwe; in sensitivity
analyses including only those surviving to the end of the
interval, HIV-exposed, uninfected infants had more than
three times as many hospital admissions for pneumonia
during the neonatal period (incidence rate ratio 3·4, 95% CI
1·9–6·0).9 HIV-exposed, uninfected infants in South Africa

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 Review

had an increased incidence of invasive pneumococcal
disease compared with HIV-unexposed infants, before and
after introduction of pneumococcal conjugate vaccine.30,31
Several studies have described pneumonia caused by an
unusually broad range of organisms in HIV-exposed,
uninfected infants, including Staphylococcus aureus,27
Escherichia coli, Pseudomonas aeruginosa, other Gram-
negative bacteria,27,32 cytomegalovirus and other viruses,27,32,33
and Pneumocystis jirovecii.24,27,34–38 Differences in outcome
might therefore be partly due to a different range of
causative organisms, which cannot be treated by standard
first-line antimicrobial regimens, or altered pathogen-
specific immune responses.
Tuberculosis
HIV-exposed, uninfected infants in developing countries
could be at greater risk of tuberculosis. In a South African
series,39 four of eight infants with congenital tuberculosis
were HIV-exposed, uninfected infants; a further two were
HIV-exposed, but did not undergo virological testing.
Compared with HIV-unexposed infants in Uganda, HIV-
exposed, uninfected infants had 2·6 times increased odds

HIV- HIV- HIV testing Feeding Outcome Result Comments

exposed, unexposed,
uninfected uninfected
infants, n infants, n
Pre-ART
Zimbabwe8 3135 9210 Mothers and EBF at 3 months: HIV-exposed 12-month mortality; HR 3·9 (95% CI Very large number of HIV-exposed
infants tested at uninfected 10·5% vs 24-month mortality 3·15–4·78), HR 2·5 on uninfected and HIV-unexposed infants;
each visit HIV-unexposed uninfected 9·3% sensitivity analysis; comparable, contemporaneous and
(NS); predominantly breastfed HR 2·0 (1·2–3·5), HR 2·0 demographically similar comparison group;
at 3 months: HIV-exposed on sensitivity analysis most infants in both groups did not
uninfected 30·6% vs exclusively breastfeed; regular HIV testing
HIV-unexposed uninfected undertaken; sensitivity analysis supported
31·9% (NS); mixed primary findings
breastfeeding at 3 months:
HIV-exposed uninfected 58·9%
vs HIV-unexposed uninfected
58·9% (NS)9
Uganda10 269 3183 Infants tested 98% breastfed; duration or 12-month mortality; RR 1·08 (NS); Small number of HIV-exposed uninfected
several times; exclusivity not reported 18-month mortality; RR 1·16, p<0·05; infants; infants rested
mothers not 24-month mortality RR 1·29 (NS) regularly—HIV-exposed uninfected group
retested unlikely to include postnatally infected
infants; mothers not retested—unexposed
group possibly included HIV-exposed
uninfected or HIV-infected infants
Zambia11 260 127 Infants tested Not stated 9-month–3-year HR 3·2 (95% CI Small number of HIV-exposed uninfected
several times; mortality 0·7–14·0), p=0·13 and HIV-unexposed infants; not followed
mothers not from birth; period of highest morbidity and
tested mortality not captured (from birth to
6 months); HR not adjusted for
confounders; mothers not
tested—exposure status determined from
infant serology (HR might therefore be
underestimated because unexposed group
might have included HIV-exposed
uninfected or HIV-infected infants);
feeding modality not stated
Rwanda12 138 209 Mothers and Majority breastfed; median of 5-year mortality HR 0·4 (95% CI 0·1–1·6), Small number of HIV-exposed uninfected
infants tested 18 months breastfeeding; p=0·20 and HIV-unexposed uninfected infants; HR
several times exclusivity not reported not adjusted for confounders; long follow-
up, but without breakdown into different
time periods
The Gambia13 258 448 Infants retested Not stated Median 6-year HIV-1 HR 1·6 (95% CI Small number of HIV-exposed uninfected
(HIV-1 64, several times; mortality; median 0·81–3·3), p=0·18; infants; HIV-1 and HIV-2-exposed
HIV-2 194) mothers not 6-year mortality HIV-2 HR 1·2 (0·70–2·0), uninfected infants included; infants
retested dependent on p=0·5; without HIV test classified as unknown;
survival to 4 months; HIV-1 HR 2·7 (1·3–5·6); unclear how missing results were
median 6-year HIV-2 HR 2·0 (1·1–3·6); treated—possibility that HIV-exposed
mortality HIV-1 HR 3·6 (1·6–8·1); uninfected group included undiagnosed
conditional on HIV-2 HR 2·2 (1·1–4·4) postnatally infected infants; feeding
survival to modality not stated; more accurate HIV
18 months status when findings conditioned on
survival to 4 months or 18 months
(Table 1 continues on next page)

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 Review

HIV- HIV- HIV testing Feeding Outcome Result Comments

exposed, unexposed,
uninfected uninfected
infants, n infants, n
(Continued from previous page)
Single dose nevirapine for PMTCT
South Africa14 936 1155 Infants tested Never breastfed: HIV-infected 12-month mortality aHR 0·77 (95% CI Large number of HIV-exposed uninfected
monthly; mothers vs 1·5% HIV-uninfected 0·49–1·21), p=0·253 and HIV-unexposed uninfected infants;
mothers not mothers HAART available before the end of the
retested 6–8 weeks EBF: HIV-infected study (unclear how many mothers
mothers 81·4% vs received HAART); only those with
HIV-uninfected 92·9% available feeding data were included; very
3–4 months EBF: HIV-infected high rates of EBF; mothers not
mothers 61·8% vs retested—unexposed group possibly
HIV-uninfected 72·6% included HIV-exposed uninfected or
HIV-infected infants; data on missing test
results unavailable
South Africa15 543 218 Infants tested 12 weeks EBF: HIV-exposed 9-month mortality HR 0·7 (95% CI 0·3–1·5) 65% of those born to mothers who died
several times; uninfected 54·7% vs HIV- not included in analyses—most at-risk
mothers not unexposed uninfected 9·4% infants possibly excluded; small number of
retested HIV-unexposed uninfected infants;
mothers not retested—unexposed group
possibly included HIV-exposed uninfected
or HIV-infected infants
Single dose nevirapine and 6 months’ infant zidovudine for PMTCT
Botswana16 534 137 Infants tested Median breastfeeding duration: 6-month mortality; HIV-exposed uninfected HIV-infected mothers breastfed for less
several times; HIV-infected mothers 24-month mortality 3·6% vs HIV-unexposed time, but significantly more were
mothers not 5·8 months vs HIV-uninfected uninfected 0·8%, exclusively breastfeeding at 5 months;
tested mothers 9·0 months; p=0·01; small number of HIV-unexposed
5 months EBF: HIV-infected HIV-exposed uninfected uninfected infants; HAART available
mothers 17·5% vs HIV- 6·7% vs HIV-unexposed before the end of the study (unclear how
uninfected mothers 9·5% uninfected 1·6%, many mothers received HAART);
p=0·002 mothers not retested—unexposed group
possibly included HIV-exposed
uninfected or HIV-infected infants;
infants lost to follow-up censored at last
HIV negative test or last study visit
Co-trimoxazole prophylaxis (HIV-exposed, uninfected infants only) and single dose nevirapine for PMTCT
Malawi, 1573 131 Infants tested Not stated 12-month mortality HIV-exposed uninfected Large number of HIV-exposed uninfected
Tanzania, several times; 7·2% vs HIV-unexposed infants; infants lost to follow-up or died
Zambia17 mothers not uninfected 4·8% (no without recent testing not included;
retested; statistical test breastfeeding not stated; small number of
possibility of performed) HIV-unexposed uninfected infants; no
HIV-exposed statistical comparisons undertaken;
uninfected mothers not retested—unexposed group
group including possibly included HIV-exposed uninfected
postnatally or HIV-infected infants; possibility of
infected infants HIV-exposed uninfected group including
postnatally infected infants
Co-trimoxazole prophylaxis (HIV-exposed, uninfected infants only) and single nevirapine and 4 weeks’ zidovudine for PMTCT
Mozambique18 158 160 Not clear if Similar feeding until 6 months; 12-month mortality OR 3·74 (95% CI Not primary trial outcome; small number
postnatally HIV HIV-unexposed uninfected 0·41–34·26), p=0·195 of HIV-exposed uninfected and
infected included breastfed for longer; HIV-unexposed uninfected infants
in analysis 100% of HIV-unexposed
uninfected breastfed to
12 months
Co-trimoxazole prophylaxis (HIV-exposed, uninfected infants only)
Uganda19 186 389 Infants tested at Breastfeeding at 6 months: 24-month mortality 13·7 (95% CI Dedicated study clinic; recruited from
several 84·4% vs 99·7%, p<0·001; 1·12–167·3), p=0·04 4 months of age; period of highest
timepoints; breastfeeding at 12 months: morbidity and mortality not recorded
mothers not 28·7% vs 98·9%, p<0·0001; (birth–4 months); adjusted for age, malaria
retested breastfeeding at 24 months: prophylaxis, breastfeeding, and wealth
0% vs 24%, p<0·0001 index

ART=antiretroviral therapy. EBF=exclusively breastfeeding. aHR=adjusted hazard ratio. NS=not statistically significant. Predominantly breastfed=breast milk and non-milk liquids. Mixed breastfed=breast milk
plus non-human milk, solid foods, or both. RR=relative risk. HR=hazard ratio. PMTCT=prevention of mother-to-child transmission. HAART=highly-active antiretroviral therapy. OR=odds ratio.

Table 1: Studies comparing mortality in HIV-exposed uninfected infants and HIV-unexposed infants

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of tuberculosis infection, diagnosed by tuberculin skin
testing or interferon-γ release assay.40
Diarrhoea
Studies from sub-Saharan Africa comparing the incidence
of diarrhoea between HIV-exposed, uninfected and HIV-
unexposed infants might partly be confounded by feeding
practices, because of changes in breastfeeding
recommendations for HIV-infected mothers over time. A
comparison between formula-fed HIV-exposed, un-
infected infants and breastfed HIV-unexposed infants in
Uganda showed a six times higher risk of severe diarrhoea
in HIV-exposed, uninfected infants at 6–11 months of
age,19 whereas in Mozambique, HIV-exposed, uninfected
infants had less diarrhoea and a similar frequency of
diarrhoea-related hospital admission as HIV-unexposed
infants, despite a shorter duration of breastfeeding.18 In
Zaire, there was a higher frequency of persistent diarrhoea
in HIV-exposed, uninfected infants compared to HIV-
unexposed infants, and results were not influenced by
feeding practices.7 After adjustment for feeding practices
in South Africa, no significant associations were recorded
between HIV exposure and acute, persistent, or overall
diarrhoea to 6 months of age.14 Where feeding practices
were similar between HIV-exposed, uninfected and HIV-
unexposed infants in Kenya, there was no difference in
frequency of diarrhoea,41 and in the ZVITAMBO trial,
where almost all infants were breastfed, HIV-exposed,
uninfected infants did not have more acute diarrhoea than
HIV-unexposed infants.9
Morbidity in developed countries
Fewer studies have assessed morbidity in HIV-exposed,
uninfected infants in developed countries, where routine
ART exposure, lower background infectious morbidity,
and a scarcity of appropriate HIV-unexposed control
groups from similar socioeconomic backgrounds make
the effect of HIV exposure harder to establish. Despite
these limitations, findings from several studies suggest
increased infectious morbidity in HIV-exposed, un-
infected infants. In a French study42 of 7638 HIV-exposed,
uninfected infants, a high proportion (699 of 7638 infants,
Kaplan-Meier estimate of 9·3%, 95% CI 8·7–10·0) were
admitted to hospital for serious infections during the
first year of life; however, no HIV-unexposed control
group was assessed and there was potential for hospital
admission bias. The most common bacterial infection
was pneumonia caused by encapsulated organisms
(Streptococcus pneumoniae and Haemophilus influenzae).
The risk was inversely associated with maternal CD4 cell
count for serious bacterial, but not viral, infections. In a
Belgian cohort, HIV-exposed, uninfected infants had
almost 20 times higher incidence of invasive group B
streptococcal disease compared with unexposed infants
in the first month of life (relative risk 19·6, 95% CI
7·5–51·7), although the absolute number of cases was
small.43 HIV-exposed, uninfected infants remained at
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Review
risk of infection over the first year of life, with 13 times
higher odds of invasive group B streptococcal disease
and four times higher odds of invasive pneumococcal
disease compared with HIV-unexposed infants.44 HIV-
exposed, uninfected infants born in the ART era had
almost three times higher morbidity than those born
before ART availability (adjusted hazard ratio [aHR]
2·93, 95% CI 1·07–8·05), whether or not mothers
actually received ART. A Danish study45 reported
increased hospital admissions in HIV-exposed, un-
infected children compared with HIV-unexposed
children in the first 4 years of life; however, this increase
was related to haematological disorders rather than
infectious diseases.
Opportunistic infections
P jirovecii pneumonia is an opportunistic infection of
HIV-infected infants, but was reported in two 7-week-old
HIV-exposed, uninfected infants from Texas in 1997.34 In
each case, infection was associated with a transient drop
in CD4 cell count. Other cases of P jirovecii pneumonia in
HIV-exposed, uninfected infants below 6 months of age
have been reported in France,42 South Africa,24,27,46 and the
USA.38 In South Africa, over half of infants admitted to
hospital with acute hypoxic pneumonia had P jirovecii
pneumonia detected using molecular techniques; HIV
exposure and malnutrition were risk factors among HIV-
uninfected infants.37 Infants in this study were thoroughly
investigated, meaning the burden of P jirovecii
pneumonia in HIV-exposed, uninfected infants else-
where might be higher than previously recognised.
Causes of increased mortality and morbidity
Despite heterogeneity in the scientific literature, the body
of evidence from various settings suggests increased
morbidity and mortality among HIV-exposed, uninfected
infants, and a risk of severe, unusual, and complicated
infections, compared with HIV-unexposed infants. The
causes of increased morbidity and mortality are probably
multifactorial, and might be partly driven by adverse
environmental and socioeconomic conditions. However,
findings are not driven purely by differences in maternal
care-taking capacity due to ill health, duration of
breastfeeding and quality of breast milk, or colonisation
or vertical transmission of pathogens.16,20,47–49 Associations
between HIV-exposed, uninfected infant mortality and
severity of maternal disease, assessed either by maternal
CD4 cell count, viral load, or mortality, have been reported
in several studies (appendix).8,47,48,50–53 Incidence of
respiratory tract infection has also been associated with
severity of maternal HIV infection in several studies.9,23,54,55
In Zimbabwe,9 infectious morbidity was high even at
maternal CD4 cell counts of more than 500 cells per μL,
and only reduced to normal with CD4 more than 800 cells
per μL. HIV-exposed, uninfected infants have
immunological abnormalities that could at least partly
account for their poor health outcomes.
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 Review
Immune dysfunction
An excellent overview of the immunology of HIV-exposed,
uninfected infants is provided in a review published in
2014.56 Here, we summarise the probable causes of immune
dysfunction in HIV-exposed, uninfected infants and
discuss additional studies published in the past few years.
Immune activation
Chronic immune activation is the hallmark of HIV
infection, and is driven by multiple factors, including HIV
itself, chronic coinfections, and intestinal microbial
translocation.57 HIV-exposed, uninfected infants are
therefore born to mothers who have high levels of pro-
inflammatory cytokines and activated T cells and B cells
during pregnancy.58 Similarly, evidence exists of immune
activation in both innate and adaptive immune cells of
HIV-exposed, uninfected infants compared with HIV-
unexposed controls. In a study of Zimbabwean infants, a
more pro-inflammatory milieu (ie, raised C-reactive
protein) was evident in HIV-exposed, uninfected infants,
compared with HIV-unexposed infants at 6 weeks of age,
and was still evident at 6 months of age (Prendergast AJ,
unpublished). HIV-exposed, uninfected infants born to
ART-treated women with undetectable viral loads had
significantly higher concentrations of pro-inflammatory
cytokines (interleukin 1β and interleukin 8) than HIV-
unexposed controls.59 By comparison with HIV-unexposed
infants, stimulated monocytes and dendritic cells secrete
higher concentrations of pro-inflammatory cytokines,60
dendritic cells have greater upregulation of the activation
markers CD80 and CD86,61 and natural killer (NK) cells
have higher expression of the activation markers CD38
(bright) and CD69 in HIV-exposed, uninfected infants.62
T cells shift towards memory (CD45RA-) and away from
naive (CD45RA+) phenotypes, have higher expression of
the activation markers CD154 and CD38, and demonstrate
greater proliferation but reduced polyfunctionality (ie,
produce fewer different cytokines) upon stimulation.63–68
Compared with HIV-unexposed controls, CD4 T cells
isolated from HIV-exposed, uninfected infants have higher
expression of inflammatory response-related chemokine
receptors (in particular CCR3 and CCR8), and in-vitro
stimulation results in upregulation of CCR8 expression
and tumour necrosis factor α.59,69 These findings suggest
an immune-priming role of HIV exposure; activated cells
are more susceptible to HIV infection in vitro, and
potentially other intracellular infections.59
T-cell number and T-cell function
HIV-exposed, uninfected infants have lower absolute
numbers of CD4 T cells, which might be due to more
apoptosis.70 In Malawi, a cohort of HIV-exposed, uninfected
infants had similar CD4 cell counts to HIV-infected infants
at 2 weeks, but not 10, weeks of age.63 In Mozambique, the
percentage of CD4 T cells was 3% lower, and CD8
percentage 1·15 times higher in HIV-exposed, uninfected
than in HIV-unexposed infants in multivariate longitudinal
e97
analysis.18 Thymic dysfunction could account for high
levels of circulating double negative (CD4– CD8–) T cells
in HIV-exposed, uninfected infants.66,71 HIV-exposed,
uninfected infants have HIV-specific T-cell responses,72
even in the context of maternal ART, which suggests that
exposure to HIV antigens takes places in utero.
Humoral immunity and vaccine responses
At birth, HIV-exposed, uninfected infants in developing
countries and developed countries have lower con-
centrations of specific antibody to vaccine-preventable
infections compared with HIV-unexposed infants.73–77
Lower concentrations of specific antibodies in
HIV-infected mothers, compounded by reduced trans-
placental transfer of antibody from mother to infant, seem
to account for the paucity of antibody in HIV-exposed, un-
infected, newborn infants,74,75,78–81 although no association
between maternal CD4 cell count or viral load and
transplacental transfer of antibody exists.74
However, responses to primary vaccination in
HIV-exposed, uninfected infants are similar (for diphtheria,
tetanus, H influenzae B, and BCG),69,74,77,82–84 or even
increased (for pertussis, pneumococcal capsular
polysaccharide, and measles),74,76,77,82,85,86 compared with
HIV-unexposed infants (table 2; appendix). Additionally,
HIV-exposed, uninfected infants have good serological
evidence of protection after combined measles, mumps,
and rubella vaccination.95 Furthermore, the fold-increase of
antibody concentration from pre-vaccination to post-
vaccination is higher among HIV-exposed, uninfected
infants compared with HIV-unexposed infants.74 An
explanation for this is reduced interference of maternally
acquired antibody with infant B-cell response to
vaccination, which has been reported for multiple vaccines.
Although the mechanism in human beings is unknown,
the mechanism in animal models seems to be due to
cross-linking of the B-cell receptor with the regulatory
receptor FcγRIIB.96 When the concentration of pre-
vaccination antibody is increased in HIV-exposed,
uninfected compared with HIV-unexposed infants, lower
concentrations are observed after immunisation.77,86 The
functionality of vaccine-specific antibody is similar in
HIV-exposed, uninfected infants and unexposed infants.73,80
These factors support the hypothesis that differences in
vaccine responses are driven by the concentration of
maternally derived antibody pre-vaccination, rather than
differences in infant B-cell function.
Birth, growth, and development
Long-term nutritional and neurodevelopmental outcomes
are influenced by environmental factors during the first
1000 days after conception—the period from conception to
2 years of age. HIV exposure during this period could
therefore crucially affect birth, growth, and development.
In developing countries, HIV-exposed, uninfected
newborn babies might be more likely to be small for
gestational age or have low birthweight compared with
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 Review

HIV-unexposed newborn babies (table 3, appendix). Low particularly because of pneumonia.55 In HIV-exposed, For more on the 1000 days
birthweight among HIV-exposed, uninfected infants is uninfected infants, preterm birth, low birthweight, and principle see http://www.
thousanddays.org
associated with 2·5–12 times higher risk of mortality,48,51,102,103 being small for gestational age were each associated with

HIV-exposed, HIV- Main findings (HIV-exposed vs HIV-unexposed) Summary

uninfected unexposed,
infants, n uninfected
infants, n
Diphtheria
South Africa77 120 114 No difference in antibody concentration or proportion of infants protected ←→
Brazil87 19 112 No difference in antibody concentration or proportion of infants protected ←→
Tetanus
South Africa74 38 55 No difference in antibody concentration ←→
South Africa77 120 114 No difference in antibody concentration or proportion of infants protected ←→
South Africa82 27 28 No differences in antibody concentration post-primary DTP, but higher concentration post-booster response in ←→ ↑
HIV-exposed uninfected infants. No differences in proportion protected
South Africa83 118 60 No difference in antibody concentration or proportion of infants protected ←→
Brazil87 19 112 Lower concentrations of specific antibody in HIV-exposed uninfected infants, but no difference in seroprotection. ↓ ←→
Uganda88 Roughly 129 Roughly 1304 Reduced interferon γ, interleukin 5, and interleukin 13 responses to tetanus toxin in HIV-exposed uninfected infants ↓
Kenya89 8 (3 months) 8 (3 months) No differences in response to TT antigens at 3 months. At 12 months, lower CD4 cell interleukin 2 response and dual ←→ ↓
26 (12 months) 17 (12 months) interleukin 2 or tumour necrosis factor α response to TT antigens in HIV-exposed uninfected infants
Pertussis (PT and FHA)
South Africa74 38 55 Higher antibody concentration in HIV-exposed uninfected infants, higher fold increase pre-vaccination to ↑
post-vaccination
South Africa77 120 114 Higher PT antibody concentration in HIV-exposed uninfected infants, but similar FHA antibody concentration. ↑ ←→
Increased proportion of HIV-exposed uninfected infants with 4 times increase in PT antibody concentration, but no
difference between HIV-exposed uninfected and HIV-unexposed uninfected infants for FHA antibody
South Africa82 27 28 Higher antibody concentration in HIV-exposed uninfected infants post-primary and pre-booster vaccines, no difference ↑ ←→
post-booster. Higher proportion of seropositive HIV-exposed uninfected infants at 6 months
South Africa83 118 60 Higher antibody concentration in HIV-exposed uninfected infants at 24 weeks, but no difference at 14 and 52 weeks. ↑ ←→
Higher proportion of seropositive HIV-exposed uninfected infants at 24 weeks
Haemophilus influenzae type b (PRP)
Uganda (HIV-exposed 57 14 Higher antibody concentration in HIV-exposed uninfected infants at 48 weeks, but no difference in avidity ↑ ←→
uninfected) and USA
(HIV-unexposed
uninfected)73
South Africa74 38 55 No difference in antibody concentration after three vaccine doses at 16 weeks, but higher fold increase pre-vaccination ←→ ↑
to post-vaccination
South Africa77 120 114 No difference in antibody concentration or SBA GMT ←→
South Africa82 27 28 No difference in vaccine responses ←→
South Africa83 118 60 Higher antibody concentration in HIV-exposed uninfected infants at 14 and 24 weeks, but no difference at 52 weeks. ↑
Higher proportion of HIV-exposed uninfected infants with protective immunity
Denmark84 19 7 No difference in vaccine responses ←→
Pneumococcal capsular polysaccharide
South Africa74 38 55 Higher antibody concentration in HIV-exposed uninfected infants, higher fold increase pre-vaccination to post- ↑
vaccination
South Africa85 120 114 No differences in GMC for serotypes ST4, 9V, 14, 18C, 19F, higher GMC for ST 6B and 23F in HIV-exposed uninfected ↑ ←→
infants after three doses of PCV. No difference in seroprotection, except for ST 6B. Similar results in OPA
South Africa76 121 116 No differences in GMC for ST 6B, 9V, 14, 18C, 19F, 23F, higher GMC for ST 4 in HIV-exposed uninfected infants after ↑ ←→ ←→
2 doses of PCV. No difference in seroprotection, except for ST 4
Similar results for most ST in OPA
Hepatitis B vaccine
South Africa77 120 114 Lower antibody concentration in HIV-exposed uninfected than HIV-unexposed uninfected infants. No difference in ↓ ←→
seroprotection
South Africa82 27 28 No difference in vaccine responses ←→
South Africa83 118 60 Lower antibody concentrations in HIV-exposed uninfected infants at 14 and 52 weeks, no difference at 24 weeks. No ↓ ←→
differences in proportion protected
Brazil87 45 112 Increased proportion of HIV-exposed uninfected infants with high responses, similar proportion with very low ↑ ←→
responses.
(Table 2 continues on next page)

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HIV-exposed, HIV- Main findings (HIV-exposed vs HIV-unexposed) Summary

uninfected unexposed,
infants, n uninfected
infants, n
(Continued from previous page)
Measles
South Africa82 27 28 No difference in vaccine responses post-primary or post-booster measles vaccine ←→
South Africa86 116 112 Post-primary vaccine: greater vaccine responses; no difference in seroprotection rates
Post-booster vaccine: no difference in vaccine responses; no difference in seroprotection rates ↑ ←→ ↓
At 2 years of age: poorer vaccine responses in HIV-exposed uninfected infants; fewer HIV-exposed uninfected infants
with seroprotection
Oral polio vaccine
Zambia90 133 397 Lower mean antibody titre in HIV-exposed uninfected infants, but no difference when breastfeeding adjusted for ←→
Malawi63 13 21 Similar median anti-polio IgG ←→
BCG
South Africa68 46 46 No difference in BCG-specific T-cell proliferation at 6 weeks; higher frequency at 14 weeks in HIV-exposed uninfected ↑ ←→ ↓
infant; decreased cytokine polyfunctionality in HIV-exposed uninfected infants
South Africa91 118 60 In infants vaccinated with BCG at birth, poorer responses to antigens in HIV-exposed uninfected infants at 14 weeks, ↓ ←→
similar responses at 24 weeks, and comparable responses at 52 weeks. Significantly lower proportion of HIV-exposed
uninfected infants produced a positive interferon-γ response to PPD compared to HIV-unexposed infants at 14 weeks.
In infants vaccinated with BCG at 14 weeks, poorer responses in HIV-exposed uninfected infants at 24 weeks, similar
responses at 52 weeks
South Africa69 47 62 No difference in BCG-specific T-cell proliferation, intracellular cytokine expression, polyfunctional T cells, or secreted ←→
cytokines
Malawi63 13 21 2 weeks: similar interferon-γ response to heat-killed BCG and PPD; 10 weeks: similar proliferation in response to heat- ←→ ↑
killed BCG, poorer proliferation in response to PPD in HIV-exposed uninfected infants; 10 weeks: similar median
anti-Mycobacterium tuberculosis IgG
Uganda88 Roughly 136 Roughly 1370 No difference in responses to crude culture filtrate proteins of Mycobacterium tuberculosis ←→
Kenya89 16 (3 months) 9 (3 months) No differences in frequency of responders to PPD antigens at either timepoint; at 3 months, increased frequency of ←→ ↑
29 (12 months) 17 (12 months) interleukin 2 or tumour necrosis factor α dual positive PPD-specific CD4 T cells in HIV-exposed uninfected infants.
Alterations in memory T-cell subsets at 3 months of age in response to PPD stimulation
South Africa92 94 12 No significant differences in BCG-specific release of interferon γ, measured by ELISA ←→
South Africa93 25 23 No difference in BCG-specific CD4 T cell cytokine response or polyfunctional cells ←→
Brazil94 58 38 Delayed BCG responses in HIV-exposed uninfected infants—by 18·1–26·3 months HIV-exposed uninfected had similar ↓ ←→
responses to HIV-unexposed uninfected infants aged 7·0–8·7 months

DTP=diphtheria, tetanus toxoid, cellular pertussis vaccine. TT=tetanus toxin. PT=pertussis toxin. FHA=filamentous haemagglutinin. PRP=polyribosyl-ribitol phosphate. SBA=serum bactericidal assay.
GMT=geometric mean titre. GMC=geometric mean concentration. OPA=opsonophagocytic activity. ST=serotypes. PCV=pneumococcal conjugate vaccine. OPV=oral polio vaccine. PPD=purified protein derivative.
Better results in HIV-exposed uninfected infants (↑); poorer results in HIV-exposed uninfected infants (↓); similar results between HIV-exposed uninfected and HIV-unexposed uninfected infants (←→).

Table 2: Comparison of vaccination responses between HIV-exposed uninfected infants and HIV-unexposed infants

at least six times higher risk of neonatal mortality, and at
least two times increased mortality up to 1 year of age.53
Data on postnatal growth in HIV-exposed, uninfected
infants are heterogeneous (appendix). Before the
availability of ART (table 3), the largest study (ZVITAMBO)
showed that HIV-exposed, uninfected infants had more
stunting (impaired linear growth), wasting (impaired
ponderal growth), and underweight than HIV-unexposed
infants throughout infancy (Evans C and Prendergast AJ,
unpublished). Length-for-age remained lower up to 12
months of age and 24 months of age in Zimbabwe (Evans
C and Prendergast AJ, unpublished) and Malawi,97
respectively (table 3). Stunting has been associated with
maternal disease severity in some studies,104,105 but not all
(Evans C and Prendergast AJ, unpublished). Impaired
growth in HIV-exposed, uninfected infants was not seen in
several, mostly smaller, studies, although many showed
non-significant trends towards poorer growth (appendix).
Investigators of a large study from South Africa,106 where
nevirapine was used for PMTCT and most infants were
exclusively breastfed, did not find a difference in weight-
for-age Z scores in the first 24 months of life. In Zambia,
HIV-exposed, uninfected infants who were breastfed had
better weight-for-age, but not length-for-age, Z scores to
15 months of age, compared with formula-fed infants.107
Large, well designed studies in the context of fully
suppressive maternal ART are needed to determine the
effect on growth in the ART era.
Interest in the impact of impoverished environments
on poor linear growth is emerging; the cleaner
environments of developed countries might mitigate
growth concerns. However, results have been hetero-
geneous. HIV-exposed, uninfected infants in the UK
were of normal length and weight compared with HIV-
unexposed infants at 3 years of age.108 Compared with
formula-fed, HIV-unexposed controls, formula-fed

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HIV-exposed, HIV- Follow-up period Main findings (HIV-exposed vs HIV-unexposed)

uninfected unexposed,
infants, n comparison
group, n
Birthweight
Zimbabwe (Evans C and Roughly 3120 Roughly 9209 24 months Mean birthweight (SD): 2·94 kg (0·46) vs 3·00 kg (0·45), p<0·05†
Prendergast AJ, unpublished)* Percentage low birthweight: 13·9% (95% CI 12·8–15·0) vs 9·9% (9·3–10·5)†; underweight at birth
(OR 1·47 [1·31–1·64])
Malawi97 270 686 24 months Significant difference in mean birthweights†
Democratic Republic of Congo98 190 256 20 months Mean birthweight (SE): 2·95 kg (0·35) vs 3·04 kg (0·32)† (p value not stated)
Mean Z score at birth (SE): 0·20 (0·07) vs −0·47 (0·07) (p value or comparison not stated)
Stunting
Malawi97 270 686 24 months Lower mean LAZ to 24 months†
Democratic Republic of Congo98 190 256 20 months No difference in mean LAZ scores to 20 months
Kenya99 155 139 18 months Mean LAZ scores: −0·48 vs −0·19, p<0·05† at 1·5 months only, otherwise similar
Rwanda100 140 207 48 months Lower mean LAZ scores only at 6 months†, not throughout rest of 48 months follow-up
Zimbabwe (Evans C and Roughly 3120 Roughly 9209 24 months Significantly lower mean LAZ to 12 months†; stunting: birth OR 1·22 (95% CI 1·08–1·38)†, 6 weeks
Prendergast AJ, unpublished)* OR 1·25 (1·11–1·41)†, 6 months OR 1·23 (1·08–1·41)†, 12 months OR 1·23 (1·08–1·39)†, 18 months
NS, 24 months NS
Uganda101 200 400 4–6 months Adjusted OR for stunting at median age of 5·2 months: 2·23, p=0·005†
(cross-sectional)
Underweight
Malawi97 270 686 24 months Lower mean WAZ to 24 months†
Democratic Republic of Congo98 190 256 20 months No difference in mean WAZ scores to 20 months
Rwanda100 140 207 48 months No difference in mean WAZ scores to 48 months
Zimbabwe (Evans C and Roughly 3120 Roughly 9209 24 months Significantly lower mean WAZ to 12 months†; underweight: at birth (see above), 6 weeks OR 1·55
Prendergast AJ, unpublished)* (95% CI 1·30–1·84)†, 6 months OR 1·52 (1·26–1·84)†, 12 months OR 1·37 (1·15–1·63)†, 18 months
NS, 24 months NS
Uganda101 200 400 4–6 months Adjusted OR for underweight at median age of 5·2 months: 1·73, p=0·09
(cross-sectional)
Wasting
Democratic Republic of Congo98 190 256 20 months No difference in mean WLZ scores to 20 months
Kenya99 155 139 18 months Mean WLZ at 6 months: 0·45 vs 0·10, p<0·05‡
Mean WLZ at 18 months: 0·16 vs −0·73, p<0·05‡
Zimbabwe (Evans C and Roughly 3120 Roughly 9209 24 months Significantly lower mean WLZ to 12 months†; wasting: birth OR 1·22 (95% CI 1·10–1·35)†, 6 weeks
Prendergast AJ, unpublished)* OR 1·58 (1·21–2·05)†, 6 months OR 1·43 (1·08–1·90)†, 12 months OR 1·56 (1·22–2·00)†, 18 months
NS, 24 months NS
Malawi97 270 686 24 months Lower mean WLZ to 24 months†
Uganda101 200 400 4–6 months Adjusted OR for wasting at median age 5·2 months: 3·29, p=0·02†
(cross-sectional)

OR=odds ratio. LAZ=length for age Z score. NS=not significant. WAZ=weight for age Z-score. WLZ=weight for length Z-score. *Total numbers of infants in the ZVITAMBO cohort differed at each time point due to
deaths, loss to follow-up, or postnatal HIV infection (infants were censored at the last negative HIV test). †Significantly poorer outcome of HIV-exposed, uninfected infants compared with HIV-unexposed
infants. ‡Significantly poorer outcome of HIV-unexposed infants compared with HIV-exposed, uninfected infants.

Table 3: Studies comparing fetal and postnatal growth in HIV-exposed, uninfected infants and HIV-unexposed infants in developing countries before the availability of ART

HIV-exposed, uninfected infants in Italy had similar
weight-for-length and weight-for-age Z scores, but lower
length-for-age Z scores at 18 and 24 months of age.109 In
the USA, ART-exposed HIV-exposed, uninfected newborn
babies had lower weight and length at birth than matched
HIV-unexposed controls, but growth accelerated during
infancy, such that anthropometric measurements were
similar by the age of 10 months.110
The effect of HIV exposure on neurodevelopment
remains uncertain. A systematic review111 identified mostly
studies with methodological shortcomings from high-
income settings without control groups. The authors
concluded that, once confounders (ie, maternal substance
misuse) were accounted for, a developmental delay was
unlikely up to 2 years of age in HIV-exposed, uninfected
infants. Authors of more studies from Malawi21 and
Colombia112 reported no significant developmental
differences at 20 and 24 months of age, respectively.
HIV-exposed, uninfected, Zimbabwean children aged
6–8 years did not have more cognitive impairment than
HIV-unexposed controls (OR 1·32, 95% CI 0·69–2·52).113
However, HIV-uninfected, Zambian children who had
been exposed to HIV in infancy had poorer mathematics,
but not English, grades at 6–12 years of age than HIV-
unexposed children after adjustment for socioeconomic
status.114 After adjustment for plausible confounders,
including carer education, HIV-exposed, uninfected
children aged 2–12 years in Thailand and Cambodia had

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 Review
poorer verbal IQ, full-scale IQ, and Stanford-Binet Bead
memory scores compared with HIV-unexposed controls,
although differences were small and their clinical
significance remains questionable.115 Results from a Thai
study116 comparing HIV-exposed, uninfected with HIV-un-
exposed children at a mean age of 10·3 years, showed no
difference in neuroanatomy or brain integrity measured
by MRI with diffusion tensor imaging, after adjustment
for socioeconomic status.
Mechanisms underlying adverse outcomes in
HIV-exposed, uninfected infants
Multiple factors could contribute to the excess risk of
morbidity, mortality, and impaired growth that has been
reported for HIV-exposed, uninfected infants.
Family environment
Children in households affected by HIV are at a high risk
of orphanhood; over 17 million children are estimated to
have lost at least one parent to AIDS since the beginning
of the HIV epidemic.117 For each woman dying of AIDS in
Africa, an average of two children are orphaned.118
Maternal mortality is associated with poor infant outcomes
regardless of the cause of death,119 because mothers who
are sick might have impaired capacity to care for their
offspring, and orphaned children might experience
extreme poverty and homelessness.120 However, the
offspring of mothers with advanced HIV infection could
be at risk of both maternal death and exacerbated immune
abnormalities,121 compounding the morbidity risk in HIV-
exposed, uninfected infants (appendix). Even in mothers
who survive, HIV infection has far-reaching consequences
for families. HIV-infected parents are at risk of poverty
because of an inability to work, which could affect food
security and access to health care for the household. HIV-
exposed, uninfected children might undertake caregiver
roles for infected family members, or could be neglected
when other children in the family are HIV-infected.
Furthermore, HIV-exposed, uninfected infants might be
brought up in an environment with greater exposure to
pathogens, including tuberculosis.122
Immune activation
Immune activation and systemic inflammation could lead
to infection susceptibility and impaired growth. Both
immune events could be explained by in-utero and postnatal
exposure to HIV. Immune activation might result from
exposure to a pro-inflammatory fetal environment or from
exposure to co-infections (such as cytomegalovirus123) or
HIV itself; HIV-exposed, uninfected infants have evidence
of HIV-specific T-cell responses,72 suggestive of in-utero
HIV exposure.124 Maternal bacterial translocation, which
causes immune activation in HIV infection,58 could directly
affect the developing immune system during fetal life,
although further studies are needed to explore this
hypothesis. Postnatal exposure to HIV through breast-
feeding might disrupt the intestinal mucosal barrier;
e101
impaired tight junction function within 2–4 h of intestinal
epithelial cell exposure to HIV was reported in in-vitro
experiments, and this dysfunction was associated with
bacterial translocation.125
Antiretroviral therapy
Prolonged exposure to ART during the developmentally
sensitive period from conception to the end of breastfeeding
could be associated with risks. A detailed discussion of
these issues is beyond the scope of this Review, but ART
could be associated with preterm birth126 and mitochondrial
toxicity.127 Associations between ART and congenital
abnormalities have been reported in some studies,128,129 but
not others.130,131 Although an association between antenatal
tenofovir and impaired postnatal growth was observed in
one US study,132 similar results have not been reported
from sub-Saharan Africa.131 A recent analysis from
Botswana showed that HIV-exposed, uninfected children
exposed to maternal combination ART had significantly
lower length-for-age and weight-for-age Z scores at
24 months than those exposed to zidovudine monotherapy.133
Interventions for HIV-exposed, uninfected infants
HIV-exposed, uninfected infants are a vulnerable
population who could benefit from additional monitoring
and interventions. Here, we review the evidence behind
existing interventions and consider the potential benefits
of additional management approaches.
Antiretroviral therapy
Since lifelong ART for pregnant and breastfeeding women
is an essential component of the efforts to eliminate
paediatric HIV infection, the benefits outweigh currently
reported risks of antenatal ART exposure. Few studies
have compared health outcomes of HIV-exposed,
uninfected infants who are either exposed or not exposed
to maternal ART, although in one study,134 an 81%
reduction in mortality to 10 years of age (aHR 0·19,
95% CI 0·06–0·59) was reported in infants exposed to
maternal ART and receiving co-trimoxazole, compared
with those without interventions. With expansion of
PMTCT Option B+, more women will conceive while on
ART, and maternal virological suppression and CD4 cell
reconstitution before pregnancy should improve the
health of HIV-exposed, uninfected infants. Longitudinal
studies of well characterised cohorts in sub-Saharan Africa
are needed to establish whether maternal ART normalises
immune function, growth, and health in HIV-exposed,
uninfected infants, or whether additional interventions
are needed.
Co-infections
Whether HIV-exposed, uninfected infants would benefit
from additional interventions to reduce P jirovecii pneu-
monia, tuberculosis, and vaccine-preventable infections is
unclear. WHO recommends co-trimoxazole prophylaxis for
all HIV-exposed, uninfected infants from 4–6 weeks of age
www.thelancet.com/infection Vol 16 June 2016

until cessation of breastfeeding,135 because of the ongoing
risk of HIV transmission and rapid disease progression in
infected infants. Although side-effects have been noted18 co-
trimoxazole is generally well tolerated in HIV-exposed,
uninfected infants, and safety data for antenatal136 and
postnatal137 co-trimoxazole support its use as a universal
intervention. In a study from Mozambique,18 HIV-exposed,
uninfected infants receiving co-trimoxazole had fewer
clinic attendances than HIV-unexposed infants not
receiving co-trimoxazole (incidence ratio 0·79, 95% CI
0·63–0·99), although in trial data from Malawi, Zambia,
and Tanzania,17 HIV-exposed, uninfected infants receiving
co-trimoxazole had 12-month mortality of 7·2% compared
with 4·8% in HIV-unexposed infants. In a non-randomised
comparison of infants in the Malawian BAN trial,138 co-
trimoxazole was associated with short-term protection
from malaria, but had no effect on a combined endpoint of
severe illness or death up to 36 weeks of age. However,
subsequent analysis found that co-trimoxazole was
associated with reductions in pneumonia, serious febrile
illness, diarrhoea, impaired growth, and malaria
throughout the first year of life.103 Although protection from
malaria is commonly reported,103,138–140 not all studies have
shown reductions in diarrhoea and pneumonia in HIV-
exposed, uninfected infants receiving co-trimoxazole, and
the risks of co-trimoxazole are argued to outweigh
benefits.141 To address this uncertainty, two randomised
trials of co-trimoxazole in HIV-exposed, uninfected infants
are underway in Botswana (ClinicalTrials.gov NCT01229761)
and South Africa (Pan-African Clinical Trials Registry
PACTR201311000621110). Interventions to prevent
tuberculosis have been unsuccessful; isoniazid preventive
therapy did not reduce tuberculosis infection in HIV-
exposed, uninfected infants in South Africa.142
Vaccinations
Vaccine responses seem to be broadly similar in
HIV-exposed, uninfected infants and HIV-unexposed
infants, which highlights the importance of timely and
complete vaccination. However, there remains a paucity
of clinical data on vaccine effectiveness in HIV-exposed,
uninfected infants.143,144 Vaccine strategies that might
mitigate the risk of infectious morbidity early in life
include antenatal immunisation, neonatal vaccination,
and earlier commencement of vaccine schedules.
However, antenatal vaccination in the context of HIV
might be associated with reduced maternal immuno-
genicity and therefore reduced transplacental transfer of
antibody to the infant,145 especially in cases of increased
maternal disease severity.146 Earlier infant vaccination
might be more efficacious; however, the feasibility of
delivering such a programme in developing countries has
not been assessed and is likely to be a barrier. In HIV-
prevalent settings, BCG should be delayed until infant
HIV status has been confirmed to avoid the vaccination
of HIV-infected infants, who are at risk of disseminated
BCG disease.147
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Review
Infant feeding
Early cessation of breastfeeding reduces HIV transmission,
but increases morbidity and mortality from other causes in
developing countries.14,51,148–153 In Zambia, reduction of the
duration of breastfeeding increased infant mortality,47 even
if weaning took place in the second year of life.51 In Uganda,
mortality was 6·2 times higher in HIV-exposed, uninfected
infants breastfed for fewer than 6 months compared with
those breastfed for longer (95% CI 1·4–27·0).151 An
association between breastfeeding cessation and mortality
and morbidity among HIV-exposed, uninfected infants
from 6 to 15 months of age was found in a Malawian trial.152
Most, but not all, studies comparing breastfeeding with
replacement feeding from birth report increased morbidity
or mortality in formula-fed infants.52,153–156 Compared with
breastfed HIV-exposed, uninfected infants, formula-fed
HIV-exposed, uninfected infants in South Africa were twice
as likely to have an illness in the first 2 months of life
(OR 2·02, 95% CI 1·16–3·51).155 In a trial156 from Burkina
Faso, Kenya, and South Africa, HIV-exposed, uninfected
infants who were formula-fed from birth had six times as
many serious infections as those who were breastfed
(adjusted OR 6·0, 95% CI 2·2–16·4). After adjustment for
infant growth and maternal disease status, breastfeeding
among HIV-exposed, uninfected infants in Kenya was
associated with 47% lower risk of pneumonia compared
with those never breastfed (HR 0·53, 95% CI 0·39–0·73).154
However, causative organisms in HIV-exposed, uninfected
infants with diarrhoea or pneumonia did not differ
according to feeding strategy in an analysis from the Mashi
trial in Botswana.32
Although replacement feeding is recommended in
PMTCT programmes in developed countries, it is only
recommended in developing countries if it is acceptable,
feasible, affordable, sustainable, and safe.157 Breastmilk of
HIV-infected women has similar levels of innate immune
factors and specific immunoglobulins as HIV-uninfected
women.16,158 Breastfeeding in the context of Option B+,
where women are on lifelong ART, leads to low levels of
HIV transmission.
Summary of trial outcomes
As progress is made towards elimination of paediatric HIV
infection, research interest in the health needs of
HIV-exposed, uninfected infants is growing. The
population remains challenging to study because of the
confounding effects of ART exposure and feeding
modality, difficulties in confirming HIV status, and a
scarcity of comparable, contemporaneous control groups.
However, the largest study, which followed over 3000 well
characterised HIV-exposed, uninfected infants before
availability of ART in Zimbabwe, showed increased
mortality,8 increased infectious morbidity,9 and impaired
growth (Evans C and Prendergast AJ, unpublished), in line
with several other well designed, but smaller,
studies.10,16,17,30,31,97,159 A South African study done in the pre-
ART era with high exclusive breastfeeding rates found no
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Panel: Suggested areas for future research in HIV-exposed, uninfected infants
Assess mortality and growth of HIV-exposed, uninfected infants in the ART era
• Clarify deleterious effects of ART exposure
• Better understand whether poorer outcomes of HIV-exposed, uninfected infants persist in
the current era, by comparison of HIV-exposed, uninfected infants exposed to ART, with
appropriate HIV-unexposed groups in developing and developed settings
Establish the causes of infection susceptibility
• Discern the effects of immunological abnormalities, maternal caretaking capabilities,
exposure to opportunistic infections, and feeding methods
• Explore the relationship between inflammation and infection susceptibility or growth of
HIV-exposed, uninfected infants
Better characterise the immune function of HIV-exposed, uninfected infants
• Assess ontogeny of the innate and adaptive immune system in HIV-exposed, uninfected
infants
• Define functional immune defects in HIV-exposed, uninfected infants using modern
immunological techniques
• Find out the effect of HIV exposure on immune activation beyond infancy and early
childhood
Evaluate the mechanisms of immune activation, inflammation, and T-cell abnormalities
• Explore the contributions of maternal or infant enteropathy, maternal or infant microbial
translocation, maternal CD4 cell count, exposure to HIV in utero or through breastfeeding,
maternal or infant co-infections, maternal or infant malnutrition, and exposure to ART
Assess the impact of immunological abnormalities on mortality or morbidity outcomes of
HIV-exposed, uninfected infants
• Correlate markers of immune dysfunction with clinical outcomes
• Better understand the timecourse of immune defects and interventions that might be
beneficial
• Establish the long-term impact of immune activation on health outcomes
Investigate the impact of co-trimoxazole
• Study the effect of co-trimoxazole on immune activation, HIV transmission, growth, and
health of HIV-exposed, uninfected infants
Infection prophylaxis and vaccination strategies
• Explore the role of additional antimicrobial prophylaxis to prevent co-infections, including
cytomegalovirus, tuberculosis, pneumocystis pneumonia
• Explore the protection provided by antenatal immunisation, neonatal vaccination, or
accelerated vaccination schedule to young infants, and the potential for modulation of
the infant’s own response to vaccination
Identification of new techniques to reduce the transmission of HIV during breastfeeding
• Breastfeeding could ameliorate some of the risks associated with HIV exposure, but HIV
transmission is still possible
ART=antiretroviral therapy.
differences in mortality14 or weight106 of HIV-exposed,
uninfected infants compared with HIV-unexposed infants,
which suggests that uptake of exclusive breastfeeding
could at least partly mitigate adverse outcomes.
Reports from developed countries suggest that, despite
maternal ART, HIV-exposed, uninfected infants remain
at increased risk of infections.42–44 Immunological abnor-
malities have been reported in HIV-exposed, uninfected
infants from both developing and developed countries.
These might persist despite maternal ART, although
e103
Search strategy and selection criteria
We searched PubMed using the terms (HIV or human
immunodeficiency virus[MeSH Terms]) AND (expos* or
uninfected or maternal or affect*[MeSH Terms]) AND (child*
or infant* or fetus or fetal or fet* or neonat*[MeSH Terms])
for English language papers between January, 1983, and
December, 2015. We reviewed reference lists of included
studies and screened abstracts from relevant conference
proceedings. Articles were selected if the infants described
were diagnosed as HIV-exposed and uninfected. A systematic
review was beyond the scope of this paper. Larger, better
quality, and newer studies with contemporaneous
comparison groups were preferentially selected, as were
systematic reviews or meta-analyses of previous data. Studies
with direct comparisons between HIV-exposed and
HIV-unexposed groups were preferentially included, whereas
studies in which the HIV status of infants was not established
with virological testing were excluded.
prospective studies of appropriate cohorts are needed to
determine the relative importance of immune function,
feeding practices, and family environment in mediating
poor outcomes of HIV-exposed, uninfected infants
(panel). Further detailed immunological analyses using
modern laboratory techniques are needed, particularly
in well characterised cohorts from sub-Saharan Africa.
Reassuringly, HIV-exposed, uninfected infants mount
robust responses to vaccination; timely vaccination is
vital to reduce the risk of vaccine-preventable infections.
HIV-exposed, uninfected infants should remain in
clinical follow-up after early infant diagnosis at 4–6
weeks of age, with repeat HIV testing after complete
cessation of breastfeeding. Although breastfeeding
increases the risk of HIV acquisition, transmission rates
in the context of fully suppressive maternal ART are low
(approximately 0·2% per month160) and prolonged
breastfeeding reduces mortality in settings where
formula-feeding is unsafe.
Conclusion
Prevention of mother-to-child transmission of HIV is an
evolving success story, although several challenges
remain in the quest to eliminate paediatric HIV.
Integration of PMTCT into broader maternal, newborn,
and child health services would meet the objective of the
improvement of child and maternal survival together.161
However, as the number of HIV-infected infants declines,
the health needs of HIV-exposed, uninfected infants
should be prioritised further, to ensure that post-2015
Sustainable Development Goals are achieved.
Contributors
CE undertook the literature review and wrote the original draft of the
paper, which was reviewed and revised by CEJ and AJP.
Declaration of interests
We declare no competing interests.
www.thelancet.com/infection Vol 16 June 2016

Acknowledgments
CE is funded by the National Institute for Health Research. AJP is funded
by the Wellcome Trust (108065/Z/15/Z).
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