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.
A Global Problem
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.
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.
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.
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 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.
Signs and Symptoms
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 www.aidsinfo.nih.gov/guidelines.
Problems in 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 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.
AIDS_info_ is a comprehensive resource for up-to-date information on government and industry sponsored HIV/AIDS treatment and prevention clinical trials. AIDS_info_ 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.
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, June 2003. 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. 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 www.unaids.org
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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