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, children and adolescents. 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. 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 the effect of HIV infection on pregnancy outcome and the natural history of HIV disease in pregnant women and their babies. 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. Many consider this finding to be one of the most significant research advances to date in the fight against HIV and AIDS.

The Scope of the Problem

The World Health Organization (WHO) estimates that by late 1995, 1.5 million children worldwide had been infected with HIV. By 2000, the WHO projects that 5 to 10 million children will have been infected with HIV, with another 5 to 10 million children orphaned by the HIV/AIDS pandemic.

In the United States, approximately 14,920 HIV-infected infants were born in the United States between 1978 and 1993, according to a recent Centers for Disease Control and Prevention (CDC) analysis. Of these, an estimated 12,240 infants were living at the beginning of 1994. Through Dec. 31, 1995, 6,948 cases of AIDS in children younger than 13, and 2,354 cases in those aged 13 through 19 had been reported to the CDC.

HIV infection ranks seventh among the leading causes of death for U.S. children one to 14 years of age. In many cities in the eastern United States, HIV disease is the leading cause of death among children ages two to five.

Transmission

Almost all HIV-infected children acquire the virus from their mothers before or during birth, a process called perinatal transmission. In the United States, approximately 25 percent of pregnant HIV-infected women not receiving AZT therapy have passed on the virus to their babies.

Most perinatal transmission, an estimated 50 to 80 percent of infections, 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 considerable research.

The risk of perinatal transmission is significantly increased if the mother has advanced HIV disease, large amounts of HIV in her bloodstream, or few of the immune system cells -- CD4+ T cells -- that are the main targets of HIV.

Other factors that may increase the risk of perinatal transmission are maternal drug use, severe inflammation of fetal membranes, or a prolonged period between membrane rupture and delivery. A recent 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.

HIV also may be transmitted from a nursing mother to her infant. A recent analysis suggested that breast-feeding introduces an additional risk of HIV transmission of approximately 14 percent. However, the WHO still recommends breast-feeding of infants in developing countries because the benefits generally far outweigh the potential risk of HIV transmission.

Prior to the screening of the nation's blood supply for HIV, 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 Perinatal HIV Transmission

A role for AZT. A study conducted by the Pediatric AIDS Clinical Trials Group 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 maternal-infant transmission by two-thirds.

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.

Researchers have subsequently shown that this AZT regimen has reduced perinatal transmission in other populations in which it has been used.

The AZT regimen used in ACTG 076 is too expensive and logistically demanding for general use in less-developed countries. Therefore, NIAID supports studies of simpler and less costly strategies for preventing mother-to-infant transmission of HIV.

Because a significant amount of perinatal HIV transmission 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. Two NIAID studies that test this hypothesis have recently begun. A study in Haiti is examining the effectiveness of a two-week course of AZT. Another study, in Uganda, will assess whether a single dose of nevirapine, given to a mother in labor when she arrives at the hospital, can prevent infection in newborns. One dose of this drug has been shown to dramatically reduce the amount of HIV in the blood.

NIAID-supported researchers also are studying whether immunoglobulin preparations containing large quantities of antibodies to HIV can prevent perinatal HIV transmission when given to the mother and/or the neonate. This strategy -- known as passive immunization -- has been used successfully in reducing perinatal transmission of hepatitis B virus.

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 show up in the standard blood test used for diagnosis of adults, this test has limited usefulness in young infants.

In the past few years, investigators have demonstrated the utility of highly accurate blood tests in diagnosing HIV infection in children six 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.

NIAID-supported scientists also are developing inexpensive tests that require less laboratory support. For instance, researchers have modified, for use in children, a test currently used in adults to detect one of the proteins in HIV's core.

NIAID-supported researchers also have demonstrated that a new kind of antibody test can diagnose HIV infection in infants as young as 3 to 6 months. This inexpensive and simple assay looks for a type of antibody known as IgA that is too large to cross the placenta. If an infant has HIV IgA antibodies, the physician knows that antibodies were actually made by the baby's immune system in response to HIV infection and did not come from the mother.

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.

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.

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, mental retardation and cerebral palsy.

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.

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 new 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 also 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 also frequently suffer from 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

Anti-HIV therapies. NIAID investigators are defining the best treatments for pediatric patients. Largely due to studies in the Pediatric AIDS Clinical Trials Group, two anti-HIV agents, AZT and didanosine (ddI), are currently approved for use in children. Two additional medications, zalcitabine (ddC) and stavudine (d4T), are available from their respective manufacturers for use in children under the Food and Drug Administration's expanded access program. Many doctors consider anti-HIV therapy for children who have HIV-related symptoms or have laboratory evidence of immunosuppression.

Recently, NIAID-supported researchers demonstrated that two treatment regimens -- ddI alone or in combination with AZT -- are each superior to AZT alone in children who have had little or no previous antiretroviral therapy. Many other antiretroviral regimens are being assessed for use in children in the Pediatric AIDS Clinical Trials Group, including various combinations of ddC, nevirapine, d4T, lamivudine (3TC), ddI and AZT. One such study, known as ACTG 300, is comparing the efficacy of AZT plus 3TC to ddI alone. The Institute also is planning clinical trials of protease inhibitors in pediatric patients, as well as novel treatment approaches such as gene therapy.

Opportunistic Infections. Many medications used to treat opportunistic infections in adults are effective in children when given in appropriate doses. For example, 85 percent of HIV-infected children are able to tolerate trimethoprim-sulfamethoxazole (TMP/SMX) for PCP. This drug is extremely effective in preventing new or recurrent PCP in children and is the first choice for pediatric patients, as it is in adult patients. NIAID studies are assessing alternative treatments to prevent PCP in children who do not benefit from or cannot tolerate TMP/SMX.

NIAID investigators are developing pediatric formulations of other agents commonly used to treat OIs, and to understand how children absorb and metabolize these drugs.

IVIG Studies. Clinical trials sponsored by NIAID and the National Institute of Child Health and Human Development (NICHD) have demonstrated that intravenous immunoglobulin (IVIG), a preparation containing many types of antibodies, can reduce bacterial infections frequent in children with AIDS. However, IVIG did not confer a survival advantage in either study, and the NIAID study suggested that the benefits of IVIG are confined to those patients who had not received TMP/SMX as preventive therapy for PCP.

AIDS in Adolescents

Adolescents account for a rapidly growing percentage of the reported AIDS cases in the United States. Although less than 1 percent of AIDS patients in the United States are between 13 and 19 years of age, this figure underestimates the significance of HIV transmission during adolescence.

Since the average period of time from HIV infection to the development of AIDS is 10 years, the majority of people in their twenties with AIDS were likely infected as adolescents. Approximately 20 percent of all reported cases of AIDS in the United States have occurred in young adults between the ages of 20 and 29.

Several recent studies have found that increasing numbers of teenagers are becoming infected with HIV, especially in poor, urban areas. Surveys of military recruits, Job Corps participants and blinded seroprevalance studies indicate that as many as one in 20 individuals aged 15 to 20 years from certain populations in the northeastern and southern United States are HIV-infected.

Psychosocial Issues

A disproportionate number of children with AIDS belong to minority groups: 84 percent of children reported with AIDS in 1995 in the United States were black or Hispanic. Most 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. 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 mother with AIDS does not survive to care for her HIV-infected child.

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

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.

National AIDS Hotline. Staffed 24 hours a day, seven days a week. (800) 342-AIDS.

The National Pediatric HIV Resource Center. (800) 362-0071.

Pediatric AIDS Coalition. (800) 336-5475.

The Pediatric AIDS Foundation. (415) 883-1796.

The Pediatric Branch of the National Cancer Institute conducts clinical trials for HIV-infected children on the NIH campus in Bethesda, Md. (301) 402-0696.

Source:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services