HIV PREVENTION AND TREATMENT
HIV in mothers and children
Melanie M Rosenvinge
Katja Doerholt
Abstract
There has been a dramatic fall in the rate of mother-to-child transmissions
(MTCTs) of human immunodeficiency virus (HIV) since the introduction of
universal HIV testing in antenatal clinics in the UK. Currently in the UK,
less than 1% of infants born to women found to be HIV-positive before
delivery will become infected. Maternal anti-retroviral therapy (ART) is
commenced in accordance with the mother’s immune status and viral
load, with the aim of achieving an undetectable viral load by delivery.
Replacement feeding effectively eliminates postnatal MTCT but, where
this is not safe, studies have shown that continuing ART for mothers or
their infants until after breastfeeding has ceased can further reduce trans-
mission. Access to effective ARTstrategies in the prevention of MTCT in low-
and middle-income countries has improved but is still only approximately
50%. ART is now initiated earlier in children and has significantly reduced
mortality and morbidity with perinatally HIV-infected children growing up
and transitioning into adult care. Unfortunately, there are still serious diffi-
culties surrounding access to paediatric formulations and adequate diag-
nostics for children in resource-poor settings. Hypervigilance for the
potential long-term toxicities of ART in children is particularly important,
as treatment initiated at a young age is currently a lifelong commitment.
Keywords anti-retroviral therapy; breastfeeding; HIV; mother-to-child
transmission (MTCT); perinatal; pregnancy; prevention
Prevention of mother-to-child transmission (PMTCT)
Introduction
Universal screening for HIV infection in all antenatal units in the
UK, introduced in 2003, has dramatically reduced MTCT. In 2011,
684,510 pregnant women (97%) were screened for HIV in En-
gland. In approximately 95% of HIV-positive pregnant women, the
Melanie M Rosenvinge MA MBBS MRCP Dip HIV DTM&H Dip GUM DFFP is a
Consultant in Genitourinary & HIV Medicine at St George’s Hospital,
London, UK. Conflicts of interest: she has received reimbursement of
expenses incurred whilst attending conferences from Abbott,
Boehringer Ingelheim, Bristol Myers Squibb Pharmaceuticals, Gilead
Sciences, MSD, Janssen and Viiv. She has also received fees for
speaking from Janssen and two research grants from Gilead Sciences.
Katja Doerholt MD MRCPCH MSc Epi is a Consultant in Paediatric Infectious
Diseases and HIV at St. George’s Hospital, London, UK. She has mainly
trained in the UK, but also worked in other European and central
African countries. She completed a Masters in Epidemiology at the
London School of Hygiene and Tropical Medicine in 2004. Research
interests are paediatric HIV, pharmacovigilance and antimicrobial use in
children. Conflicts of interest: none declared.
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What’s new?
C Use of maternal viral load to guide start-time for anti-retroviral
therapy (ART) in pregnancy
C If a woman conceives while taking an effective ART regimen, the
balance of risk is generally thought to be in favour of continuing
the successful regimen through the pregnancy rather than
changing it
C Where the benefits of breastfeeding outweigh the risks of for-
mula feeding, studies show that mother-to-child transmission is
reduced if the mother continues to take ART, or ART prophylaxis
is given to the infant until after breastfeeding has finished
C ART is now started in children at higher CD4 counts compared
to historic guidelines
C Late diagnosis of perinatally HIV-infected adolescents is
increasingly reported; they are often clinically well but have low
CD4 counts.
diagnosis is made before delivery, and three-quarters of these are
aware of their HIV status before becoming pregnant.1 As a
consequence, only 30e40 children are perinatally infected with
HIV each year in the UK, with fewer than 10 transmissions
occurring where the mother was found to have HIV before de-
livery. The mother’s HIV status may remain unknown if she de-
clines screening, accesses antenatal services late or becomes
infected with HIV during pregnancy/breastfeeding.1 By contrast,
in low- and middle-income countries, only an estimated 35% of
pregnant women underwent HIV testing and counselling in 2010,
with 48% of HIV-positive pregnant women being treated with the
most effective PMTCT regimens.2 Hence, in 2011, approximately
330,000 children were newly infected with HIV worldwide.
Although this represents a decline of 43% since 2003,3 there is
clearly much more to be achieved in this area.
HIV transmission
Without any interventions the risk of MTCT is thought to be
between 20 and 40%, depending on the population. The most
striking risk factor is the maternal viral load (VL). If this is un-
detectable at delivery the risk of MTCT is 0.1% (Table 1). The
routes of transmission are as follows.
Intrauterine: in utero infection is more common towards the end
of pregnancy and may be associated with placental disruption by
chorioamnionitis.
Intrapartum: transmission could occur via direct contact with
infectious maternal blood and genital secretions during birth or
alternatively maternalefetal micro-transfusion may occur during
contractions. Prolonged labour and rupture of membranes rupture
may increase the risk of MTCT. Pre-labour caesarean section
(PLCS) alone has been shown to reduce the risk of HIV trans-
mission by 80%.4 This is usually performed at 38e39 weeks.
During lactation: breastfeeding approximately doubles the
MTCT rate (36.7% compared to 20.5% who were formula-fed)
(Table 1).5
461 Ó 2013 Elsevier Ltd. All rights reserved.
 HIV PREVENTION AND TREATMENT
Low rates of mother-to-child transmission of HIV: UK &
Ireland 2000e2006 (Townsend CL et al. AIDS 2008; 22:
973e981)
Group Number of transmissions
Overall 61/5151
More than 14 days of cART 40/4864
AZT þ PLCS 0/464
cART þ PLCS 16/2286
cART þ SVD 4/559
VL <50 copies/ml at 3/2117 (*2 with evidence
delivery of in utero transmission)
AZT, zidovudine; cART, combination anti-retroviral therapy; CI, confidence in-
terval; HIV, human immunodeficiency virus; MTCT, mpther-to-child transmis-
sion; PLCS, planned lower caesarean section; SVD, spontaneous vaginal
delivery; VL, viral load.
(Copyright of National Study of HIV in Pregnancy and Childhood. Reproduced
with kind permission. www.ucl.ac.uk/nshpc/slides)
Table 1
Current interventions to reduce transmission
Anti-retroviral therapy (ART): what ART is chosen and when it is
started depends on the mother’s treatment history, whether they
have conceived while taking medication, how much is known about
the safety of the drug regimen, their baseline viral load and when
they first present. The aim is to prevent transmission whilst also
avoiding maternal/fetal toxicity and compromising future maternal
options of therapy. The following advice is based on the UK 2012
British HIV Association (BHIVA) guidelines.6 In low-income set-
tings, decisions will be more affected by the available resources.
When to start ART in pregnancy: women who need ART for their
own health should commence cART (combination anti-retroviral
therapy) as soon as possible. Women should commence tempo-
rary ART by 24 weeks and ideally by the beginning of the second
trimester if their viral load is over 30,000 copies/ml. The aim is an
undetectable viral load by delivery, which is less likely with a high
baseline viral load.7 cART may be started early if pre-term delivery
is likely or amniocentesis is planned.
Which maternal ART combination? three agents (usually two
nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-
nucleoside reverse transcriptase inhibitor (NNRTI) or protease
inhibitor (PI)) should be used. The exception is if the mother has
a CD4 count over 350/ml and a viral load of less than 10,000
copies/ml, and is happy to have a PLCS when zidovudine
monotherapy is an option. Mutations associated with resistance
to zidovudine are unusual in this setting.8
Women who present late or with high baseline viral load
should be considered for a regimen including raltegravir, which
is associated with a rapid decline in viral load.9 Those presenting
with a detectable viral load in labour should also be considered
for a stat dose of nevirapine and an infusion of zidovudine. In
pre-term labour, the mother may be given additional ART that
effectively crosses the placenta in order to preload the neonate.
Single-dose nevirapine should not be used in isolation as it is
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associated with the development of a high rate of resistance,
compromising the mother’s future ART options.10
Infant post-exposure prophylaxis (PEP): all infants should
receive PEP. Where the maternal viral load is under 50 copies/ml
MTCT
at delivery, the infant should receive zidovudine monotherapy
rate (%)
for 4 weeks. Where it is more than 50 copies/ml, then a three-
drug regimen should be initiated. PEP should be given ideally
1.2
within 2 hours of birth (<72 hours) and continued for 4 weeks
0.8
post-partum. Options may be reduced in pre-term neonates
0.0
where oral absorption can be difficult, toxicities are more likely
0.7
and zidovudine is the only intravenous drug widely available.
0.7
0.1
Mode of delivery: where a mother’s viral load is under 50
copies/ml at delivery, there is no advantage of PLCS over vaginal
delivery. If viral load is over 400 copies/ml at 36 weeks, then a
PLCS is recommended. For low-level viraemia, the decision will
depend on length of time on treatment, trajectory of viral load
and maternal adherence to ARVs.
Feeding: replacement feeding eliminates postnatal MTCT but it is
an option only where it is safe for the infant. Where formula
feeding is not advised, the WHO recommends exclusive breast-
feeding for 6 months, then continued breastfeeding until 12
months, stopped gradually over 1 month.11 ART should be
continued for the mother or child during the breastfeeding period
as it significantly reduces transmission.12,13 In the UK, if the
mother is very keen to breastfeed and has an undetectable viral
load with high adherence to cART, she should be counselled
thoroughly regarding the risks involved. If she decides to
breastfeed, she should be closely supported with frequent
monitoring of her viral load and additional testing of her baby.
Safety of ARV drugs
Whilst prospective safety data on the use of ART in pregnancy is
limited, it is generally accepted that there is no increase above
the expected background prevalence of defects for neonates
exposed to the majority of agents. Where possible, new agents
are avoided as there are fewer data surrounding their use in
pregnancy. Those who conceive while taking effective cART
should generally continue, with the exception of PI monotherapy
or cART including stavudine or didanosine. There are no routine
dose alterations in pregnancy. Nevirapine should not be started if
the woman has a CD4 count of more than 250/ml because of the
risk of serious rash or hepatotoxicity. There are concerns that use
of PIs is associated with an increased risk of premature birth and
more information about this is needed.14
Short-term toxicities of ART drugs in neonates include
anaemia, lactic acidosis and adrenal dysfunction.15 Lopinavir/ri-
tonavir can cause gastrointestinal disturbance and deaths have
been seen in pre-term neonates secondary to its co-formulation
with ethanol in combination with overdosing. Long-term effects
for neonates exposed to ART drugs are still not fully understood.16
Infant testing
The UK guidelines recommend testing during first 48 hours, at 6 and
12 weeks of age, and on other occasions if risks such as breast-
feeding are known, with a confirmatory test if the initial test is
positive.6 HIV DNA or RNA can be used for viral testing; clearance
462 Ó 2013 Elsevier Ltd. All rights reserved.
 HIV PREVENTION AND TREATMENT

lymphadenopathy, recurrent bacterial infections, diarrhoea and

Pneumocystis jirovecii pneumonia
failure to thrive. Bilateral, persistent parotid enlargement is a
useful sign of HIV infection. Older children can present with a
pattern of disease similar to adult disease, with severe bacterial
or opportunistic infections, or focal organ disease (e.g. isolated
cardiomyopathy, chronic renal failure). A small proportion will
not present until adolescence and often have a low CD4 count at
diagnosis despite being clinically asymptomatic.21

Figure 1 Chest computed tomography scan of Pneumocystis jirovecii
pneumonia in an infant. Note patchy ground-glass shadowing and cystic
change. (From Sharland M, Bryant PA. Paediatric HIV infection. Medi-
cine 2009; 37(7): 371e373.)
of maternal antibodies should be confirmed at 18e24 months.
If virological testing is unavailable, WHO recommends a clinical
algorithm for infants under 18 months with positive serology.17
Paediatric HIV infection
Clinical features
Before the advent of ART, the European Collaborative Study
showed that 10e20% of vertically infected children present in
the first 2 years of life with rapidly progressing HIV disease, and
50% progress to AIDS or die by the age of 10 years.18 Low CD4
percentage and young age are associated with progression to
AIDS and death.19,20 In low-income settings, if CD4 count is not
available, other predictors such as weight for age or haemoglobin
can be used.20
In infants, Pneumocystis jirovecii pneumonia (PCP) is the most
common opportunistic infection and can lead to severe respira-
tory failure (Figure 1). Outcomes have improved with earlier
diagnosis and improved management in intensive care. Pre-
school children commonly present with widespread
Management
About 20 different anti-retroviral drugs are currently available for
children. After starting cART, immune reconstitution is faster in
younger children (often less than 1 year in those under 2 years of
age), but can take years in school-aged children. The Children with
HIV Early Anti-retroviral Therapy (CHER) Study showed that
starting cART under 1 year of age regardless of CD4 count signifi-
cantly reduces mortality.22 This practice has been adopted world-
wide.2,20,23 In older age groups, WHO,24 US25 and European23
guidance differ in precise recommendations (Table 2) but, overall,
commencing ART is now advised at higher CD4 counts. Achieving
this in low- and middle-income settings is challenging where only
28% of eligible 0e14-year-olds received cART in 2011.3
The Arrow and DART trials, in children over 4 years and adults in
low-income countries, showed increased mortality, mainly due to
bacterial infections, among those with low CD4 values in the first 3
months after starting cART.26 Paediatric data from high-income
settings have shown that most children on cART remain very
well, and mortality has decreased dramatically by 80%, and
morbidity by 50%, since the introduction of cART in 1996.27 Most
affected children will now live well into mid-adult life. As yet, it is
unclear how the long-term risks of toxicity (lipodystrophy, hyper-
lipidaemia, etc) will affect the children later in life.
For most paediatric ART, there are major problems with the
taste and/or size of syrups and tablets, which can impair
adherence. Adherence to treatment is a challenge, particularly
through adolescence, and maintenance of psychological health is
important. Increasingly, children with HIV infection are aware of
their diagnosis earlier in life.
The future
Treatment with cART is a lifelong commitment and therefore
pharmacovigilance is vital to identify long-term toxicities in children

Criteria for starting ART in children according to WHO, PENTA23 and US guidance26
Age WHO 2010 PENTA 2009 US 2012

<2 years <18 months and presumptive All <1 year

clinical diagnosis of HIV 1e3 years with CD4 <1000/ml or <25%
2e5 years CD4 <750/ml or <25% 3e5 years with CD4 <500/ml or <20% 3e5 years with CD4 <750/ml or <25%
>5 years CD4 <350/ml CD4 <350/ml or CD4 350e500/ml if viral
load >100,000 copies/ml
Clinical criteria Start ART for all children with WHO stage 3 or 4 or CDC stage B or C Start children >1 year who have mild
symptoms with CD4 counts higher than
levels above

ART, anti-retroviral therapy; CDC, US Centers for Disease Control and Prevention (CDC); PENTA, Paediatric European Network for Treatment of AIDS; WHO, World Health
Organization.

Table 2

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 HIV PREVENTION AND TREATMENT
and young adults. There remain serious issues about equality of
access for both first- and second-line ART drugs and adequate di-
agnostics for infants and children in the resource-poor setting. A
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Practice points
Prevention of mother-to-child transmission
C Consider repeat testing for HIV in the third trimester of preg-
nancy in those at higher risk of HIV
C Initiate anti-retroviral therapy (ART) in all pregnant women by
24 weeks’ gestation. Those with baseline viral load >30,000
copies/ml should commence combination anti-retroviral therapy
(cART) at the beginning of the second trimester and those who
need it for their own health should start as soon as possible
C Vaginal delivery is advocated for women who have an unde-
tectable viral load at delivery
C Administer post-exposure prophylaxis immediately after de-
livery to all neonates born to HIV-positive mothers. Continue for
4 weeks post-partum
464 Ó 2013 Elsevier Ltd. All rights reserved.
 HIV PREVENTION AND TREATMENT

C Recommend replacement feeding where safe

C Where replacement feeding is not safe, continue the mother/
infant’s ART until 1 week after exposure to breast milk has
ended

Paediatric HIV
C Test infants born to women with HIV for HIV DNA or RNA in the

first 2 days, and at 6 and 12 weeks, with an antibody test at 18

months and additional testing if breastfed
C Start co-trimoxazole in newly diagnosed infants and those at

high risk of infection

C Start cART in all infants <1 year of age

C Start cART in children >1 year according to guidelines (Table 2)

C Continue education, and adherence and psychological support

throughout treatment, with close monitoring of toxicities such

as lipids, lipodystrophy, and bone metabolism

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