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Page 1 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
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.
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