HIV
Infection in Infants and Children
The National Institute of Allergy and Infectious Diseases (NIAID)
has a lead role in research devoted to children infected
with HIV (human immunodeficiency virus), the virus that
causes AIDS (acquired immunodeficiency syndrome). NIAID-supported
researchers are developing and refining treatments to
prolong the survival and improve the quality of life of
HIV-infected infants and children through the Pediatric AIDS
Clinical Trials Group (PACTG). The PACTG is a nationwide
clinical trials network jointly sponsored by NIAID and the
National Institute of Child Health and Human Development (NICHD).
NIAID also supports research on ways to prevent
mother-to-child transmission (MTCT) of HIV through the PACTG
and its HIV Prevention Trials Network (HPTN), a global
clinical trials network designed to test promising
nonvaccine strategies to prevent the spread of HIV/AIDS.
In this era of antiretroviral therapy, epidemiologic
studies such as NIAID's Women and Infant's Transmission
Study (WITS) are examining risk factors for transmission as
well as the course of HIV disease in pregnant women and
their babies. Researchers have helped illuminate the
mechanisms of HIV transmission, the distinct features of
pediatric HIV infection, and how the course of disease and
the usefulness of therapies can differ in children and
adults.
According to UNAIDS (The Joint United Nations Programme on
HIV/AIDS) at the end of 2003, an estimated 2.5 million
children worldwide under age 15 were living with HIV/AIDS.
Approximately 500,000 children under 15 had died from the
virus or associated causes in that year alone. As HIV
infection rates rise in the general population, new
infections are increasingly concentrating in younger age
groups.
December 2003 UNAIDS/World Health Organization (WHO)
worldwide statistics show
- 700,000 children under age 15 were newly infected
with HIV
- Thirteen percent of all new HIV infections were in
children under age 15
- Three million children in sub-Saharan Africa, the
region with the highest number of cases, are living with
HIV
More than 95 percent of all HIV-infected people now live
in developing countries, which have also suffered 95 percent
of all deaths from AIDS. In those countries with the highest
prevalence, UNAIDS predicts that, between 2000 and 2020, 68
million people will die prematurely as a result of AIDS. In
seven sub-Saharan African countries, mortality due to
HIV/AIDS in children under age five has increased by 20 to
40 percent. Life expectancy for a child born in Botswana,
the country with the highest HIV prevalence in the world,
has dropped below 40 years-a level not seen in that country
since before 1950.
The United States has a relatively small percentage of
the world's children living with HIV/AIDS. From the
beginning of the epidemic through the end of 2002, 9,300
American children under age 13 had been reported to the
Centers for Disease Control and Prevention (CDC) as living
with HIV/AIDS. The vast majority of HIV-infected children
acquire the virus from their mothers before or during birth
or through breast feeding. Because of the widespread use of
AZT and other highly active antiretroviral therapy (HAART)
in HIV-infected pregnant women in the United States, only 92
new cases of pediatric AIDS were reported in 2002. More than
three times that number are infected with HIV but have not
yet developed AIDS.
- The U.S. city with the highest rate of pediatric
AIDS through 2002 was New York City, followed by Miami,
FL, and Washington, DC.
- The disease disproportionately affects children in
minority groups, especially African Americans. Out of
9,300 cases in children under 13 reported to the CDC
through December 2002, 59 percent were
black/non-Hispanic, 23 percent were Hispanic, 17 percent
were white/non-Hispanic, and less than 1 percent were in
other minority groups.
New anti-HIV drug therapies and promotion of voluntary
testing continue to positively effect the death rate. CDC
reported a drop of 68 percent from 1998 to 2002 in the
estimated number of children who died from AIDS.
TRANSMISSION
Almost all HIV-infected children acquire the virus from
their mothers before or during birth or through
breastfeeding. In the United States, approximately 25
percent of pregnant HIV-infected women not receiving AZT
therapy have passed on the virus to their babies. The rate
is significantly higher in developing countries.
Prior to 1985 when screening of the nation's blood supply
for HIV began, some children as well as adults were infected
through transfusions with blood or blood products
contaminated with HIV. A small number of children also have
been infected through sexual or physical abuse by
HIV-infected adults.
PREGNANCY AND BIRTH
Most MTCT, estimated to cause more than 90 percent of
infections worldwide in infants and children, probably
occurs late in pregnancy or during birth. Although the
precise mechanisms are unknown, scientists think HIV may be
transmitted when maternal blood enters the fetal circulation
or by mucosal exposure to virus during labor and delivery.
The role of the placenta in maternal-fetal transmission is
unclear and the focus of ongoing research.
The risk of MTCT is significantly increased if the mother
has advanced HIV disease, increased levels of HIV in her
bloodstream, or fewer numbers of the immune system
cells-CD4+ T cells-that are the main targets of HIV.
Other factors that may increase the risk are maternal
drug use, severe inflammation of fetal membranes, or a
prolonged period between membrane rupture and delivery. A
study sponsored by NIAID and others found that HIV-infected
women who gave birth more than 4 hours after the rupture of
the fetal membranes were nearly twice as likely to transmit
HIV to their infants, as compared to women who delivered
within 4 hours of membrane rupture.
BREASTFEEDING
HIV also may be transmitted from a nursing mother to her
infant. Studies have suggested that breastfeeding introduces
an additional risk of HIV transmission of approximately 10
to 14 percent among women with chronic HIV infection. In
developing countries, an estimated one-third to one-half of
all HIV infections are transmitted through breastfeeding.
WHO recommends that all HIV-infected women be advised
about both the risks and benefits of breastfeeding for their
infants so they can make informed decisions. In countries
where safe alternatives to breastfeeding are readily
available and economically feasible, this alternative should
be encouraged. In general, in developing countries where
safe alternatives to breastfeeding are not readily
available, the benefits of breastfeeding in terms of
decreased illness and death due to other infectious diseases
greatly outweigh the potential risk of HIV transmission.
PREVENTING MOTHER-TO-CHILD TRANSMISSION
In 1994, a landmark study conducted by the PACTG
demonstrated that AZT, given to HIV-infected women who had
very little or no prior antiretroviral therapy and CD4+
T-cell counts above 200/mm3, reduced the risk of
MTCT by two-thirds, from 25 percent to 8 percent. In the
study, AZT therapy was initiated in the second or third
trimester and continued during labor, and infants were
treated for 6 weeks following birth. AZT produced no serious
side effects in mothers or infants. Long-term follow up of
the infants and mothers is ongoing.
A few years later, another PACTG study found that the
risk of transmitting HIV from an HIV-positive mother to her
newborn infant could be reduced to 1.5 percent in those
women who received antiretroviral treatment and appropriate
medical and obstetrical care during pregnancy.
Combination therapies have been shown to be beneficial in
treating HIV-infected adults, and current guidelines have
been designed accordingly. In HIV-infected pregnant women,
the safety and pharmacology of these potent drug
combinations need to be better understood, and NIAID is
conducting studies in this area.
The AZT regimen is not available in much of the world
because of its high cost and logistical requirements. The
cost of a short-course AZT regimen is substantially lower,
but is still prohibitive in many countries. International
agencies are studying whether there may be innovative ways
to provide AZT at lower cost, for example, through
reductions in drug prices to developing countries or
partnerships with industry. As a result, NIAID continues to
evaluate other strategies that may be simpler and less
costly to prevent MTCT in various settings. In September
1999, one such study demonstrated that short-course therapy
with nevirapine lowered the risk of HIV-1 transmission
during the first 14 to16 weeks of life by nearly 50 percent
compared to AZT in a breastfeeding population. As a follow
up, NIAID released a final report on additional data showing
that the results of nevirapine were sustained after 18
months. These findings have significant implications because
this simple, inexpensive regimen offers a potential
cost-effective alternative for decreasing MTCT in developing
countries.
In addition, in April 1999 the International Perinatal
HIV Group reported that elective caesarian section delivery
can help reduce vertical transmission of HIV, though it is
not without risk to certain women. When AZT treatment is
combined with elective caesarian delivery, a transmission
rate of 2 percent has been reported.
Because a significant amount of MTCT occurs around the
time of birth, and the risk of maternal-fetal transmission
depends, in part, on the amount of HIV in the mother's
blood, it may be possible to reduce transmission using drug
therapy only around the time of birth. NIAID has planned
other studies that will assess the effectiveness of this
approach as well as the role of new antiretrovirals,
microbicides and other innovative strategies in reducing the
risk of MTCT of HIV.
HIV infection is often difficult to diagnose in very young
children. Infected babies, especially in the first few
months of life, often appear normal and may show no telltale
signs allowing for a definitive diagnosis of HIV infection.
Moreover, all children born to infected mothers have
antibodies to HIV, made by the mother's immune system, that
cross the placenta to the baby's bloodstream before birth
and persist for up to 18 months. Because these maternal
antibodies reflect the mother's but not the infant's
infection status, the test for HIV infection is not useful
in newborns or young infants.
In recent years, investigators have demonstrated the
utility of highly accurate blood tests in diagnosing HIV
infection in children 6 months of age and younger. One
laboratory technique, called polymerase chain reaction (PCR),
can detect minute quantities of the virus in an infant's
blood. Another procedure allows physicians to culture a
sample of an infant's blood and test it for the presence of
HIV.
Currently, PCR assays or HIV culture techniques can
identify at birth about one-third of infants who finally and
ultimately prove to be HIV infected. With these techniques,
approximately 90 percent of HIV-infected infants are
identifiable by 2 months of age, and 95 percent by 3 months
of age. One innovative new approach to both RNA and DNA PCR
testing uses dried blood spot specimens, which should make
it much simpler to gather and store specimens in field
settings.
Researchers have observed two general patterns of illness in
HIV-infected children. About 20 percent of children develop
serious disease in the first year of life; most of these
children die by age 4. The remaining 80 percent of infected
children have a slower rate of disease progression, many not
developing the most serious symptoms of AIDS until school
entry or even adolescence. A report from a large European
registry of HIV-infected children indicated that half of the
children with perinatally acquired HIV disease were alive at
age nine. Another study of 42 perinatally HIV-infected
children, who survived beyond 9 years of age, found about
one-quarter of the children to be asymptomatic with
relatively intact immune systems.
The factors responsible for the wide variation observed
in the rate of disease progression in HIV-infected children
are a major focus of the NIAID pediatric AIDS research
effort. WITS is a multisite perinatal HIV study. It has
found that maternal factors, including Vitamin A level and
CD4+ T-cell counts during pregnancy, as well as infant viral
load and CD4+ T-cell counts in the first several months of
life, can help identify those infants at risk for rapid
disease progression who may benefit from early aggressive
therapy.
Many children with HIV infection do not gain weight or grow
normally. HIV-infected children frequently are slow to reach
important milestones in motor skills and mental development
such as crawling, walking, and talking. As the disease
progresses, many children develop neurologic problems such
as difficulty walking, poor school performance, seizures,
and other symptoms of HIV encephalopathy (a brain disorder).
Like adults with HIV infection, children with HIV develop
life-threatening opportunistic infections (OIs), although
the incidence of various OIs differs in adults and children.
- Toxoplasmosis (a parasitic disease) is seen less
frequently in HIV-infected children than in HIV-infected
adults, while serious bacterial infections occur more
commonly in children than in adults.
- Pneumocystis carinii pneumonia (PCP) is the leading
cause of death in HIV-infected children with AIDS. PCP,
as well as cytomegalovirus (CMV) disease, usually are
primary infections in children, whereas in adults these
diseases result from the reactivation of latent
infections.
- A lung disease called lymphocytic interstitial
pneumonitis (LIP), rarely seen in adults, occurs more
frequently in HIV-infected children. This condition,
like PCP, can make breathing progressively more
difficult and often results in hospitalization.
- Severe candidiasis, a yeast infection that can cause
unrelenting diaper rash and infections in the mouth and
throat that make eating difficult, is found frequently
in HIV-infected children.
- As children with HIV become sicker, they may suffer
from chronic diarrhea due to opportunistic pathogens.
Children with HIV suffer the usual childhood infections
more frequently and more severely than uninfected children.
These infections can cause seizures, fever, pneumonia,
recurrent colds, diarrhea, dehydration, and other problems
that often result in extended hospital stays and nutritional
problems.
While the basic principles that guide treatment of pediatric
HIV infection are the same as for an HIV-infected adult,
there are a number of unique scientific and medical concerns
that are important to consider in treating children with HIV
infection. These range from differences in age-related
issues such as CD4+ T-cell counts and drug metabolism to
requirements for special formulations and treatment regimens
that are appropriate for infants through adolescents. As in
adults, treating HIV-infected children today is a complex
task of using potent combinations of antiretroviral agents
to maximally suppress viral replication. NIAID investigators
are defining the best treatments for pediatric patients.
NIAID-supported researchers are focusing not only on the
development of new antiretroviral products but also on the
critical question of how to best use the treatments that are
currently available, especially in resource-poor nations.
Treatment strategy questions should be designed to identify,
for example, the best initial therapy, when failing regimens
should be modified, and strategies to address the
antiretroviral needs of children with advanced disease.
Another high priority is the long-term assessment of these
strategies to determine sustained antiretroviral benefits as
well as to monitor for potential adverse consequences of
treatment. Current guidelines for the use of antiretroviral
agents in pediatric HIV infection is available at
http://www.aidsinfo.nih.gov/guidelines.
A mother and child with HIV usually are not the only family
members with the disease. Often, the mother's sexual partner
is infected, and other children in the family may be
infected as well. Frequently, a parent with AIDS does not
survive to care for his or her HIV-infected child.
In the countries hardest hit by the AIDS epidemic, some
14 million children under 15 around the world have been
orphaned by AIDS-80 percent of them (11 million) in
sub-Saharan Africa alone. The rate is expected to increase.
One in three of these orphans is under age five. Communities
and extended families are struggling with and often
overwhelmed by the vast number of children orphaned by AIDS.
Many orphans and other children from families devastated by
AIDS face multiple risks, such as forced relocation,
violence, living on the streets, drug use, and even
commercial sex. Other children suffer because sexuality
education and services are not available to them or not
effectively communicated to them. Living in a country
undergoing political turmoil or can also raise the risk of a
child becoming HIV-infected.
In the United States, most children living with HIV/AIDS
live in inner cities, where poverty, illicit drug use, poor
housing, and limited access to and use of medical care and
social services add to the challenges of HIV disease.
One encouraging note is, according to UNAIDS, that where
information, training, and services to help prevent HIV
infection are made available and affordable, young people
are more likely to make use of them than their elders.
Management of the complex medical and social problems of
families affected by HIV requires a multidisciplinary case
management team, integrating medical, social, mental health,
and educational services. NIAID provides special funding to
many of its clinical research sites to provide for services,
such as transportation, day care, and the expertise of
social workers, crucial to families devastated by HIV.
AIDSinfo is a comprehensive resource for up-to-date
information on government and industry sponsored HIV/AIDS
treatment and prevention clinical trials. AIDSinfo
also maintains the most current, federally approved
guidelines for treating and preventing HIV/AIDS in adults
and children, for AIDS-related illnesses, managing
occupational exposure to HIV, and for preventing HIV
transmission from mother-to-child during pregnancy.
AIDSinfo is sponsored by the NIH Office of AIDS
Research, NIAID, National Library of Medicine, CDC, Health
Resources and Service Administration, and Centers for
Medicare and Medicaid Services.
AIDSinfo
P.O. Box 6303
Rockville, MD 20849-6303
1-800-HIV-0440 (1-800-448-0440)
301-519-0459
1-888-480-3739 (TTY/TDD)
Monday to Friday, 12:00 p.m. to 5:00 p.m. Eastern Time
http://aidsinfo.nih.gov
OTHER INFORMATION RESOURCES
National Library of Medicine
MedlinePlus
8600 Rockville Pike
Bethesda, MD 20894
1-888-FIND-NLM (1-888-346-3656)
301-594-5983
http://www.medlineplus.gov
Centers for Disease Control and Prevention
CDC-INFO
1600 Clifton Road
Atlanta, GA 30333
1-800-CDC-INFO (1-800-232-4636)
1-888-232-6348 TTY
http://www.cdc.gov
Centers for Disease Control and Prevention
National Prevention Information Network
P.O. Box 6003
Rockville, MD 20849-6003
1-800-458-5231 or 301-562-1098
1-800-243-7012 or 301-588-1589 TTY
http://www.cdcnpin.org
SELECTED CITATIONS
Guidelines for the Use of Antiretroviral Agents in Pediatric
HIV Infection, June 2003.
http://www.aidsinfo.nih.gov/guidelines
Public Health Service Task Force Recommendations for Use
of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for
Maternal Health and Interventions to Reduce
Perinatal HIV-1 Transmission in the United States, June
2003.
http://www.aidsinfo.nih.gov/guidelines
UNAIDS. AIDS Epidemic Update, December 2003
UNAIDS The Report on the Global HIV/AIDS Epidemic.
Focus: AIDS and orphans. July 2002. p. 133
http://www.unaids.org
Connor, E., et al. 1994. Reduction of maternal-infant
transmission of human immunodeficiency virus type 1 with
zidovudine treatment.
N Engl J Med
311:1173
Marseille, E., et al. 1999. Cost effectiveness of
single-dose nevirapine regimen for mothers and babies to
decrease vertical HIV-1 transmission in sub-Saharan Africa.
Lancet
654:803
Riley, L.E. and Green, M.F. . 1999. Elective caesarean
delivery to reduce the transmission of HIV.
N Engl J Med
340:13, 1032
Stiehm, E., et al. 1999. Efficacy of zidovudine and human
immunodeficiency virus (HIV) hyperimmune immunoglobulin for
reducing perinatal HIV transmission from HIV-infected women
with advanced disease: results of Pediatric ACTG protocol
185. J
Infect Dis 179(3):567
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