HIV Infection in Infants and Children

Overview

The National Institute of Allergy and Infectious Diseases (NIAID) has a lead role in research devoted to children infected with the human immunodeficiency virus (HIV), the virus that causes the acquired immunodeficiency syndrome (AIDS).

NIAID-supported researchers are developing and refining treatments to prolong the survival and improve the quality of life of HIV-infected infants and children. Many promising therapies are being tested in the Pediatric AIDS Clinical Trials Group (ACTG), a nationwide clinical trials network jointly sponsored by NIAID and the National Institute of Child Health and Human Development (NICHD). Scientists also are improving tests for diagnosing HIV infection in infants soon after birth so that therapy can begin as soon as possible.

Epidemiologic studies are examining risk factors for transmission as well as the course of HIV disease in pregnant women and their babies in an era of antiretroviral therapy. Researchers have helped illuminate the mechanisms of HIV transmission as well as the distinct features of pediatric HIV infection and how the course of disease and the usefulness of therapies can differ in children and adults.

Researchers also are studying ways to prevent transmission of HIV from mother to infant. Notably, Pediatric ACTG investigators have demonstrated that a specific regimen of zidovudine (AZT) treatment, given to an HIV-infected woman during pregnancy and to her baby after birth, can reduce maternal transmission of HIV by two-thirds.1 Many consider this finding to be one of the most significant research advances to date in the fight against HIV and AIDS.

A Global Problem

According to UNAIDS (The Joint United Nations Programme on HIV/AIDS) and the World Health Organization (WHO),2,3 at the end of 1998, an estimated 1.2 million children worldwide under age 15 were living with HIV/AIDS. Approximately 3.2 million children under 15 had died from the virus or associated causes. The number of children who had lived with HIV from the start of the epidemic through 1997 was estimated to be 3.8 million. As HIV infection rates rise in the general population, new infections are increasingly concentrating in younger age groups.

Statistics for the year 1998 alone show that

590,000 children under age 15 were newly infected with HIV.
One-tenth of all new HIV infections were in children under age 15.
Approximately 7,000 young people aged 10 to 24 became infected with HIV every day-that is, five each minute.
Nine out of 10 new infections in children under 15 were in sub-Saharan Africa.
An estimated 510,000 children under 15 died of AIDS-related causes, up from 460,000 in 1997.


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 countries with the longest-lived AIDS epidemics, some doctors report that children ill from HIV occupy three-quarters of pediatric hospital beds, and childrens' life expectancy has been shortened dramatically. In Botswana, for example, because of AIDS, the life expectancy of children born early in the next decade is just over age 40; without AIDS, it would have been 70. In Namibia, the infant mortality rate is expected to reach 72 deaths per 1000, up from a non-AIDS rate of 45 per 1000.

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 1998, 5,237 American children under age 13 had been reported to the Centers for Disease Control and Prevention (CDC) as living with HIV/AIDS.4 Three hundred eighty-two cases of pediatric AIDS were reported in 1998.5 There are many more children who are infected with HIV but have not yet developed AIDS. Half of all new HIV infections reported to the CDC have been in people younger than 25.6 One encouraging fact is that the number of pediatric AIDS cases estimated by the CDC fell by two-thirds from 1992 to 1997 (947 to 310 cases).7

The U.S. cities that had the five highest rates of pediatric AIDS during 1998 were New York City; Miami, Florida; Newark, New Jersey; Washington, D.C.; and San Juan, Puerto Rico.8 The disease disproportionately affects children in minority groups, especially African Americans.9 Out of 8,461 cases in children under 13 reported to the CDC through December 1998, 58 percent were in blacks/not-Hispanic, 23 percent were in Hispanics, 17.5 percent were in whites/not-Hispanic, and 5.33 percent were in other minority groups.10

According to 1996 data, the latest available, HIV infection was the seventh leading cause of death for U.S. children through 14 years of age.11 However, the CDC reported a drop of 56 percent from 1994 to 1997 in the estimated number of children who died from AIDS.12 New anti-HIV drug therapies and promotion of voluntary testing are having a major impact.

Transmission

Almost all HIV-infected children acquire the virus from their mothers before or during birth or through breast-feeding. 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 higher in developing countries.

Most mother-to-child transmission, estimated to cause over 90 percent of infections worldwide in infants and children,13,14 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 maternal-infant transmision (MIT) 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 four 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 four hours of membrane rupture.15

HIV also may be transmitted from a nursing mother to her infant. Studies have suggested that breast-feeding introduces an additional risk of HIV transmission of approximately 10 to 14 percent among women with chronic HIV infection.16 In developing countries, an estimated one-third to one-half of all HIV infections are transmitted through breast-feeding.17 The WHO recommends that all HIV-infected women be advised as to both the risks and benefits of breast-feeding of their infants so that they can make informed decisions. In countries where safe alternatives to breast-feeding are readily available and economically feasible, this alternative should be encouraged. In general, in developing countries where safe alternatives to breast-feeding are not readily available, the benefits of breast-feeding in terms of decreased illness and death due to other infectious diseases greatly outweigh the potential risk of HIV transmission.

Prior to 1985 when screening of the nation's blood supply for HIV began, some children 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.

Preventing Maternal-Infant Transmission (MIT)
In 1994, a landmark study conducted by the Pediatric ACTG 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 MIT by two-thirds, from 25 percent to 8 percent.18 In the study, known as ACTG 076, AZT therapy was initiated in the second or third trimester and continued during labor, and infants were treated for six weeks following birth. AZT produced no serious side effects in mothers or infants. Long-term follow-up of the infants and mothers is ongoing. Pediatric ACTG protocol 185 tested an AZT regimen and was reported in 1999 to have lowered MIT to about 5 percent.19 Combination therapies have been shown to be beneficial in the treatment of HIV-infected adults, and current guidelines have been designed accordingly.20 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.

Researchers have shown that this AZT regimen has reduced MIT in other populations in which it has been used. Observational studies in the past few years in the United States and Europe indicate that similar reductions can be achieved by using this regimen in regular clinical care settings. In the U.S., the number of MIT-acquired AIDS cases reported to the CDC fell 43 percent from 1992 to 1996, probably because of providing AZT to HIV-infected mothers, better guidelines for prenatal HIV counseling and testing, and changes in obstetrical management.21,22

Recent studies have shown that short regimens, too, of AZT can be beneficial in cutting back on MIT. In March 1999, researchers reported on a randomized study in Thailand on the short-term use of AZT during late pregnancy and labor in a group of non-breast-feeding women (the drug was not given to infants). They concluded that the treatment was safe and effective and can reduce the rate of MIT by 50 percent.23 Another recent study using a short-term AZT regimen (including post-partum) in groups of women in Ivory Coast and Burkina Faso, Africa, while limited, supported this finding.24

Following up on the success of ACTG 076, the Pediatric ACTG has begun new HIV prevention trials that build on the AZT regimen. These trials include other antiviral agents and multidrug combinations in an attempt to reduce MIT even more than that achieved by AZT alone. Also, in early 1999, a study sponsored by UNAIDS of a combination regimen of AZT plus lamivudine (3TC) in three African countries showed promising results.25

The AZT regimen used in ACTG 076 is not available in much of the world because of its high cost (approximately $1000 per pregnancy, not counting counseling or testing) and logistical demands. 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, e.g., through reductions in drug prices to developing countries, partnerships with industry, etc. NIAID is pursuing a global strategy that assesses whether simpler and less costly regimens to prevent mother-to-infant HIV transmission can be effective in various settings.

In September 1999, an NIAID-funded study (HIVNET 012) demonstrated that short-course therapy with nevirapine lowered the risk of HIV-1 transmission during the first 14-16 weeks of life by nearly 50 percent compared to AZT in a breastfeeding population.26 This simple, inexpensive regimen offers a potential cost-effective alternative for decreasing mother-to-child transmission in developing countries.27.

The International Perinatal HIV Group reported in April 1999 that elective caesarean section delivery can help reduce vertical transmission of HIV, though it is not without risk to certain women.28 When AZT treatment is combined with elective caesarean delivery, a transmission rate of 2 percent has been reported.29

Because a significant amount of MIT 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 MIT of HIV.


Diagnosis

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 exhibit no telltale signs that would allow 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 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 are truly 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.


Progression of HIV Disease in Children

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 years.

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 recent 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 9. 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. The Women and Infants Transmission Study, a multisite perinatal HIV study funded by NIH, has found that maternal factors including Vitamin A level and CD4 counts during pregnancy, as well as infant viral load and CD4 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.

Signs and Symptoms of Pediatric HIV Disease
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 speaking. As the disease progresses, many children develop neurologic problems such as difficulty walking, poor school performance, seizures, and other symptoms of HIV encephalopathy.

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. For example, toxoplasmosis 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. Also, as children with HIV become sicker, they may suffer from chronic diarrhea due to opportunistic pathogens.

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, also occurs frequently in HIV-infected children. This condition, like PCP, can make breathing progressively more difficult and often results in hospitalization.

Children with HIV suffer the usual childhood bacterial infections -- only more frequently and more severely than uninfected children. These bacterial infections can cause seizures, fever, pneumonia, recurrent colds, diarrhea, dehydration and other problems that often result in extended hospital stays and nutritional problems.

HIV-infected children frequently have severe candidiasis, a yeast infection that can cause unrelenting diaper rash and infections in the mouth and throat that make eating difficult.


Treatment of HIV-Infected Children
NIAID investigators are defining the best treatments for pediatric patients. Currently there are 16 drug products approved by the FDA for the treatment of adult HIV infection. Through major contributions by the Pediatric ACTG, 10 antiretroviral agents have pediatric label information, including 3 protease inhibitors.28 While the basic principles that guide treatment of pediatric HIV infection are the same as for any HIV-infected person, there are a number of unique scientific and medical concerns that are important to consider in the treatment of children with HIV infection. These range from differences from adults in age-related issues such as CD4 lymphocyte counts and drug metabolism to requirements for special formulations and treatment regimens that are appropriate for infants through adolescents. As in adults, treatment of HIV-infected children today is a complex task of using potent combinations of antiretroviral agents to maximally suppress viral replication.

Researchers supported by NIAID 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. Treatment strategy questions designed to identify what the best initial therapy is, when failing regimens should be switched and strategies for how to address the antiretroviral needs of children with advanced disease are examples. Long-term assessment of these children is also a high priority to assess sustained antiretroviral benefits as well as to monitor for potential adverse consequences of treatment.


Problems of Families
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 8.2 million children under 15 around the world have been orphaned by AIDS - 90 percent of them in sub-Saharan Africa alone.31 The rate is expected to increase. One in three of these orphans is under age five.32 Communities and extended families are struggling with and often overwhelmed by the vast number of AIDS orphans. 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 sex education and services are not available to them or do not communicate effectively to them. Living in a country undergoing political turmoil or where fathers migrate for work can also raise the risk of a child becoming HIV-infected.

In the U.S., 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 that, according to UNAIDS, where information, training, and services to help prevent HIV infection are made available and affordable to young people, they are more likely to make use of them than their elders are.33

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.


Resources
Note: The UNAIDS and CDC publications referenced in this article may be viewed on the World Wide Web at http://www.unaids.org and http://www.cdc.gov.

AIDS Clinical Trials Information Service. For information about pediatric and adult AIDS clinical trials open to enrollment, call (800) TRIALS-A, 9 a.m. to 7 p.m. Eastern Time, Monday through Friday. Web: http://www.actis.org E-mail: actis@actis.org.

National AIDS Hotline. Staffed 24 hours a day, seven days a week. English Service: 1-800-342-AIDS. Spanish service: 1-800-344-7432. Deaf service (TDD): 1-800-243-7889.

The National Pediatric HIV Resource Center. A non-profit organization that serves professionals who care for children, adolescents and families with HIV infection and AIDS. Phone: 973-972-0410 or toll free: 1-800-362-0071. Web: http://pedhivaids.org/. E-mail: ortegaes@umdnj.edu.

The Pediatric AIDS Foundation. A national non-profit organization dedicated exclusively to supporting reseach for AIDS in children. Phone: 310-314-1459. Web: http://www.pedaids.org E-mail: info@pedaids.org.

The Pediatric Branch of the National Cancer Institute (NCI) conducts clinical trials for HIV-infected children on the NIH campus in Bethesda, Md. Phone: (301) 402-0696. NCI webpage: http://www.nci.nih.gov


References
Connor, E. et al. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 311:1173-80.
UNAIDS. AIDS Epidemic Update (Dec., 1998):1, 2, 3, 7, 8., 9, 17.
UNAIDS. Report on the Global HIV/AIDS Epidemic (June, 1998):6, 8.
Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report (Dec. 1998) 10(2):7.
Ibid., p. 26
Rosenberg, P., et al. 1994. Declining age at HIV infection in the United States. N Engl J Med 330:789-90.
Centers for Disease Control and Prevention, op cit., p. 36.
Ibid., pp. 10-11.
UNAIDS, Update, p. 6.
Centers for Disease Control and Prevention, op. cit., p. 24.
Centers for Disease Control and Prevention. National Center for Health Statistics. 1998. National Vital Statistics Report 47 (9):26.
Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report, p. 39.
NAIDS, Report.
Quinn, T. 1996. Global burden of the HIV pandemic. Lancet:348:99-106.
Landesman, S., et al. 1996. Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. N Engl J Med 334: 1617-23.
Monitoring the AIDS Pandemic (MAP) Network. 1998. The status and trends of the HIV/AIDS epidemics in the world:17.
UNAIDS, Report, p. 48.
Connor, E., et al., op. cit.
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 Pedatric ACTG protocol 185. J Infect Dis 179(3):567-75.
Centers for Disease Control and Prevention. 1998. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR Recommendations and Reports 47 (RR-2). May be viewed on the Web at http://www.hivatis.org.
Wilfert, C., et al. 1999. Consensus statement: Science, ethics, and the future of research into maternal infant transmission of HIV-1. Lancet 353 (9155):832-35.
Centers for Disease Control and Prevention. 1997. Update: Perinatally acquired HIV/AIDS-United States, 1997. MMWR 46: 1086-92.
Shaffer, N., et al. 1999. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomised controlled trial. Lancet 353 (9155):773-79.
Dabis, F. et al. 1999. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso. Lancet 353 (9155):786-92.
Saba, J., The PETRA Trial Study Team. 1999. Interim analysis of early efficacy of three short course ZDV/3TC combination regimens to prevent mother-to-child transmission of HIV-1. Presented at the Sixth Conference on Retroviruses and Opportunistic Infections. Chicago: February 1, 1999.
Guay, L, et al. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354:795-802.
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 654:803-09.
Riley, L.E. and Green, M.F. Elective caesarean delivery to reduce the transmission of HIV. 1999. N Engl J Med 340:13, 1032.
Mofenson, L.M., Fowler, M.G. In press. Interruption of materno-fetal transmission. Reported in Shaffer, N., op. cit.
HIV/AIDS Treatment Information Service. 1999. Guidelines for the use of antiretroviral agents in pediatric HIV infection. May be viewed on the Web at http://www.hivatis.org/.
UNAIDS, Report, p. 9.
Centers for Disease Control and Prevention. National Center for HIV, STD, and TB Prevention. Divisions of HIV/AIDS. International Projections/Statistics. Web: http://www.cdc.gov/hiv/stats.htm#international
UNAIDS, Update, p. 9.

NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, and other infectious diseases as well as asthma and allergies.