Pediatric HIV Infection.

Abstract

HIV infection by maternal transmission is increasing in the world due to the increase in infected women who are not receiving appropriate antiretroviral therapy. Prognosis of HIV infection in children is poor because the newborn has an immature immune system. Early diagnosis and therapy are needed to avoid the development of AIDS. New therapies are becoming available but prevention of infection, through maternal therapy during pregnancy, is the most effective measure in avoiding this infection through this transmission route.

Full text

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REVIEW ARTICLE
Vol. 3, No. 4, December 2004 IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY /159
Pediatric HIV Infection

Teresa Espanol, Isabel Caragol, Pere Soler, and Manuel Hernandez

Department of Immunology and Immunodeficiencies, Hospital Vall d´Hebron, School of Medicine,
Barcelona, Spain

ABSTRACT

HIV infection by maternal transmission is increasing in the world due to the
increase in infected women who are not receiving appropriate antiretroviral therapy.
Prognosis of HIV infection in children is poor because the newborn has an immature
immune system. Early diagnosis and therapy are needed to avoid the development of
AIDS. New therapies are becoming available but prevention of infection, through
maternal therapy during pregnancy, is the most effective measure in avoiding this
infection through this transmission route.

Keywords: Anti Retroviral Agents; Antigens, CD4; HIV; Vertical Transmission


INTRODUCTION

The number of HIV infected people is increasing
worldwide:1,2 In 2003, 5 million new cases, of whom
half were women under 30 years of age, were added
to the infected population. Less than 15% of HIV-
infected people have access to therapy. This situation
leads to an increase in mother-to-child-transmission
(MTCT) which has very poor prognosis: 800,000 new
cases and 600,000 deaths were reported in 2003.
Available effective prevention measures3,4 include
therapy applied during pregnancy, at delivery and in
the post-partum period;5 nevertheless, infections in
children are increasing and mortality remains very
high6 if no antiretroviral therapy is applied.
Many questions are yet to be resolved regarding
susceptibility to infection including measures for
immune protection in different populations and
different situations.7 However, it has been very clearly
demonstrated that viral load at delivery (and, as a
direct relationship, CD4 number and maternal status)
are predictive of viral transmission.8 Furthermore, the
very good results obtained with antiretroviral therapy
(AR) in pregnant women with low viral load at deli-
very confirm that viral transmission is almost nil.9,10

Corresponding Author: Dr. Teresa Espanol,
Department of Immunology and Immunodeficiencies, Hospital Vall
d´Hebron, School of Medicine, Barcelona, Spain. Tel: (+34 93) 274
6832, Fax: (+34 93) 274 6831, E-mail: tespanol@vhebron.net
Factors which contribute to the poor prognosis of
MTCT of HIV infection, include:
• Immaturity of the newborns´ immune system and
more so if they are premature or the infection occurs
intrautero.11
• Lack of immunologic memory, thus, each contact
with any infectious agent will lead to an immune
response that will, as a consequence, give rise to viral
replication and shedding, thereby infecting new CD4
cells. Viral load in children is always higher than in
infected adults and is more difficult to control.12

Our Experience
In our hospital, a 350-bed pediatric hospital (NHS
and University hospital), we have diagnosed, treated
and followed around 100 infected children and 500
children born of HIV-positive mothers since 1984.
Two clear-cut periods can be distinguished: the first
between our first case and the beginning of triple
therapy with anti-proteases in 1997, and the second
since then.
In the first period we had many more cases with
severe forms of presentation and very short mean life
span.13 The first patient was referred to our Unit with
suspected congenital immunodeficiency (SCID). He
had disseminated CMV infection and hypogamma-
globulinemia. Although we ruled out a SCID after
immunological evaluation, and HIV had been very

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recently described, no definitive diagnosis could be
made until antigen detection tests became available (1
year after he died). Other cases of hypogamma-
globulinemia have been reported, but HIV infection in
the mothers had previously been diagnosed.
Two main patterns of disease presentation were
observed:
Pattern 1: when symptoms began before the age of
6 months, with P. Carinii, CMV or other
opportunistic infections, life expectancy was very
short14 and death before 2 years of age was the most
common outcome.
Pattern 2: when the patients presented with
lymphoid proliferation, bacterial infections, etc and
were diagnosed late, prognosis was better. The oldest
surviving patient infected by MTCT and with good
clinical status was born in 1981.15
We considered these two patterns to correspond to
intrautero pattern 111 or perinatal infection pattern 2.16
Other authors17 refer to a bi-modal distribution.
A recent meta-analysis on prognosis revealed
similar data and emphasized the relationship between
CD4´s and viral load. Prognosis is clearly worse with
the same CD4 number if the child is under 2 years of
age.

Diagnosis of Infection and Immunodeficiency
Status

A- Diagnosis of HIV infection:
In the early years of the epidemic, infected
newborns and infants were diagnosed using the co-
culture techniques18 and detection of p24 in
supernatants, with a very high predictive value mainly
in those who were asymptomatic with good CD4
levels. In children older than 12 months, serology and
viral load by molecular biology techniques are the
currently used diagnostic tests with high sensitivity
and specificity.19 Other less expensive methods have
been described but their use depends on the socio-
economic circumstances in each country.

B- Diagnosis of immunodeficiency:
Blood cell count, lymphocyte subsets, mainly CD4
number considering age difference,20 Ig levels and,
when possible, lymphocyte activation markers,
complete the picture of the situation in each patient
and aid the decision of the best anti-retroviral (AR)
protocol.
The CDC classification21 is not often used when
therapy is initiated, and controls and therapeutic
decisions are based on CD4 numbers and viral load.
Other immunological
investigated to ascertain the different susceptibility to
this infection in the population, and very interesting
results have been obtained. Among them, mutations in
the CCR5 co-receptor correlate with a less severe
disease22,23 and provide new insights into the
pathogenesis of this disease.
HLA genotyping also shows interesting corre-
lation with progression and severity of the infection.24

Eradication of MTCT
Several measures are to be implemented in order
to decrease very significantly the incidence of MTCT:

a) Therapy during pregnancy and at delivery:
Control of viral load during gestation must be
accompanied by serology, detection of other infect-
ions such as CMV, toxoplasmosis, tuberculosis, etc.
Therapy protocols vary if the pregnant woman is
already on AR therapy or is not., and recommend-
ations have been published. The wide use of
Zidovudine (protocol 076)9 in the last months of
pregnancy, during labor and in the first weeks of the
newborn´s life has led to a clear reduction in MTCT.
However, a greater reduction is achieved if combi-
nations with three drugs are implemented (up to 0.6%
in Spain last year).

b) Caesarean section:
It has been shown to decrease transmission of the
infection25 by avoiding the entry of blood cells from
the mother into the fetus´s blood during labor and
delivery.

c) Avoiding breastfeeding:
The risk of HIV transmission to infants through
breast milk outweighs the dangers associated with
other nursing methods.

Adverse Effects of AR Therapy During Pregnancy
A few cases of neurologic syndrome associated
with persistent mitrochondrial dysfunction in children
born to seropositive mothers and exposed to anti-
retrovirals26 have been described. Obviously, different
drugs are being studied with a view to avoiding this
toxicity, but the percentage of this adverse effect
markers have been

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versus the high number of non-infected newborns,
thanks to these preventive measures, advocates the
use of these protocols.

Treatment of HIV Infection
Treatment protocols of HIV infection have
changed enormously in the last 10 years, and major
advances have been made in the management of
pediatric HIV patients in the last 2 years,27 thanks not
only to the advent of new drugs (that are aiding
therapy of other viral infections) but also to the
information derived from many research studies on
AR drugs.
Prior to AR therapy, we observed that children
with late presentation of HIV infection and who had
mainly bacterial infections benefited from gamma-
globulin therapy28 since immune stimulation was
decreased and thus, as we now know, viral
replication. This treatment, together with treatment of
demonstrated infections (P. carinii, CMV, bacterial
infections, etc) and infection prevention (prophylactic
antibiotics in cases with low CD4 numbers) were the
only measures available. Zidovudine therapy (we
treated our first pediatric patient in 1987) produced a
significant improvement in disease progression and
particularly neurologic manifestations. However, the
following protocols with two AR drugs and, as a
complete change in the history of this disease, triple
therapy with one or two protease inhibitors, also
called HAART29,30, have led to effective control of
viral replication, and therefore CD4 cell destruction
and thus have nearly stopped the evolution to AIDS
with quite good quality of life in the large majority of
patients.
The combination of two nucleoside analogues
with one protease inhibitor is the standard protocol to
begin therapy in a newly diagnosed child with low
CD4 cells and high viral load: if the child is under 12
m. of age with CD4<25-30% and viral load >106 and
after 12 months when viral load is over 250.000 RNA
particles. Monotherapy is not useful, thus many other
combinations can be used.

Follow-up
Thymic dysfunction and involution are markers of
immunodeficiency and rapid progression in infected
children. The use of T-cell receptor excision cycles
(TRECs) in treated children as a measure of new
thymic emigrants (Cells that emigrate /go out from
the thymus to the periphery) has confirmed the main
role of these new T cells (naive cells). Immune
restoration,31 with this method, following potent AR
therapy, has been clearly demonstrated.
Patients who have access to HAART therapy are
now considered to have a chronic HIV infection and
although a complete clearing of the virus has never
been achieved, they can lead a normal life. Although a
few reports exist on malignancies in children, mainly
lymphomas32 in patients with severe immuno-
depression and high viral load, overall life expectancy
is very high and intercurrent diseases are very rare.
It is also true that some problems derived from
HAART exist:
Medication must be taken rigorously. Adherence
must be complete; if not, the risk of resistant virus33 is
very high.
There are also adverse effects of therapy (gastro-
intestinal, pancreatic, lipid metabolism , etc).
There are other infections after long periods on
AR therapy (mycobacteria, bacteria resistant to
antibiotics, etc) but most are related to viral-resistant
strains and the difficulty in controlling viral load.

New Perspectives
New AR drugs are under investigation34 and some
new ways to avoid infection are already in use. Anti-
fusion drugs to avoid the attachment of viral particles
to the cell are showing promising results.
Therapeutic vaccines35 to be used in infected
subjects to increase their immune reponse are under
investigation and would be a means of keeping the
virus under control. A preventive vaccine is proving
very elusive36,37 although much research is being
devoted to it.
However, prevention continues to be the best way
of avoiding infection and its consequences.

CONCLUSION

This very important global health and population
problem is leading to the loss of a whole generation of
young people, which will make it very difficult for
many countries to develop economically owing to the
loss of work forces in coming decades.
With respect to MTCT, it is now clear that the
adequate treatment and control of pregnant women
are the only way to improve the overall situation:
fewer infected babies and healthier mothers. From the

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financial point of view, it is less expensive to treat the
mothers during pregnancy and to avoid MTCT than to
treat the infected children for the rest of their lives.38
However, in epidemics such as HIV infection,
political decisions are essential to define health policy
in each country.

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