Since the first report of an infant with acquired immunodeficiency syndrome (AIDS) in November 1982,1 the incidence of human immunodeficiency virus type 1 (HIV-I) infection among US children has increased exponentially. A national population-based HIV seroprevalence study estimated 1800 infants per year acquire HIV perinatally in the United States.2 Cumulatively, 32 172 cases of AIDS in women have been reported to the Centers for Disease Control and Prevention (CDC) through December 1992.3 More than 80% of these women are of childbearing age. During the same time period, 4249 cases of pediatric AIDS were reported, most (>80%) resulting from vertical transmission of HIV from their mothers. Infection through transfusion of HIV-contaminated products rarely occurs in regions of the world where the blood supply is screened. Thus, in the United States, as in most of the world, pediatric HIV infection reflects the prevalence of HIV infection in women of childbearing age.
VERTICAL TRANSMISSION OF HIV: REVIEW OF PUBLISHED DATA
Less than one third of children born to HIVinfected women acquire HIV infection.4,5 A recent large prospective study reported a transmission rate of 14%. Most of the women in this study were asymptomatic. In comparison, women with symptomatic HIV disease or AIDS may have an increased rate of HIV transmission.
Human immunodeficiency virus may be transmitted from mother to infant during gestation, during birth, or after birth by breast-feeding. Although the timing of HIV transmission has not been fully elucidated, HIV can be found in the blood by culture or polymerase chain reaction (PCR) in approximately 33% to 50% of infected infants within days of birth. These infants are thought to have acquired HIV in utero.6 The remaining infants are thought to contract HIV in the peripartum period.
A working definition of the timing of maternalfetal transfer of HIV infection recently has been developed.7 In utero infection refers to when a child born to an HIV-infected mother is found to be HIV positive by culture or PCR within 48 hours of birth, and repeat viral culture or PCR are positive. Human immunodeficiency virus infection is classified as intrapartum if the viral culture or PCR are negative in the first week of life and the subsequent tests are positive.
Human immunodeficiency virus has been found in amniotic fluid, in fetal blood, and from fetal tissues. It has been isolated in trophoblast cells and in some term placentas, especially in placental Hofbauer cells, which are of macrophage lineage. Human immunodeficiency virus-infected cells can be found in the placenta of many HIV-infected women; however, their presence is not directly related to the risk of transmission of HIV to the infant.8'10 While the role of the placenta in protection is unclear, it is likely that such a role exists. Women who have active syphilis in pregnancy appear to be more likely to transmit HIV to their infants, possibly secondarily to a placentitis from Treponema pallidum or other infections.1 1 Studies of the pregnant macaque infected with simian immunodeficiency virus (SIV) support a role for placentitis in increasing the transmission of SlV to the offspring.12
Exposure of the infant's mucosal surfaces and traumatized skin to blood and cervical secretions during birth is thought to be the mode of infection for many infants. Data supporting HIV transmission from mother to infant during the peripartum period include a higher infection rate in the firstborn twin, regardless of whether birth was vaginal or by caesarean section.13,14 The presenting twin had a threefold greater risk of infection than did the secondborn twin. These data suggest that the presenting twin is more likely to become HlV infected because of a longer exposure to infected blood and cervical secretions or an increased incidence of trauma in the genital tract during labor and delivery.
A number of maternal factors are proposed to influence the rate of HlV transmission from mother to child.5,15"20 An increased viral burden, measured by p24 antigenemia (an HIV protein), a low CD4 cell number, an advanced clinical disease state, and the absence of maternal antibody to specific HIV epitopes have been associated with an increased risk of transmission.
The role of maternal immunity in protecting the infant from perinatal transmission of HIV is unclear. Several reports have suggested that the frequency of perinatal HIV transmission is decreased in women who have antibodies directed against gpl20, one of the viral envelope proteins.21"23 Specifically, these reports suggest that women who have antibody to the third region of the variable ( V3 ) loop of gpl 20 are less likely to transmit HIV to their offspring. The genetic sequence variation, and thus the antigen structure, coded by the V3 region is considerable, even within an individual. Human immunodeficiency virus neutralizing antibodies bind to the V3 region, and one's repertoire of antibodies may not always recognize all variants of one's HIV population.
A Swedish study evaluated the neutralizing activity of maternal sera to homologous as well as heterologous viral isolates in a small number of mother and infant pairs.24 Nontransmitting mothers were able to neutralize homologous as well as heterologous virus. None of the mothers who transmitted HIV had neutralizing activity to their child's viral isolate. These data suggest that selective vertical transmission may occur when neutralization-resistant viral variants develop under immune pressure in the mother.
A number of studies have looked for human genetic determinants of HIV disease expression. A study from Scotland found certain HLA haplotypes to be more frequent in HIV-infected compared with non-HIVinfected infants.25 A US study evaluated susceptibility to HIV infection in 106 African- American perinatally exposed infants from New York City and San Francisco.26 A "risky" allele in the infant was associated with an increased rate of HIV infection. Thus, certain genetic factors may affect susceptibility and resistance to HIV infection.
There have been a limited number of reports of infants infected with HIV by breast-feeding; their mothers seroconverted to HIV after delivery of the infant. The reported transmission rates for these groups range from 6.3% to 27%. 27'29 The seroconverting women are experiencing primary infection with HIV, which is thought to present an increased risk of transmission compared to chronic HlV infection. While the World Health Organization promotes breast-feeding in areas where safe alternatives are not generally available, the CDC recommends that HIVinfected American women not breast-feed.
STRATEGIES TO INTERRUPT PERINATAL TRANSMISSION OF HIV-I INFECTION
A number of interventions have been proposed that may decrease the rate of perinatal HIV transmission. These include:
* decreasing the HIV viral load of the infected pregnant woman by antiretroviral therapies,
* maintaining placental integrity by treatment or prophylaxis of genital tract infections,
* providing passive anti-HIV antibody to the pregnant woman, fetus, and newborn, and
* active or passive enhancement of fetal and neonatal anti-HIV specific immunity.
The National Institutes of Health through the AIDS Clinical Trials Group (ACTG) is sponsoring an ongoing multicenter trial (ACTG Protocol 076) to assess the protective effect of zidovudine (ZDV, formerly AZT) in preventing vertical transmission of HIV. Trie pregnant woman is randomized to ZDV or placebo in the second trimester of pregnancy, receives an intravenous infusion of the same (ZDV or placebo) during labor, and the infant takes the same (ZDV or placebo) for 6 weeks postpartum. Interim analysis of data from this occurs regularly, and the trial will be halted if a protective effect is offered by ZDV.
Aggressive diagnosis and treatment of genital tract infections during pregnancy is recommended to decrease inflammation and tissue friability, which may pose an added risk of HIV infection to the infant. Various approaches to the diagnosis and treatment of genital tract infections during pregnancy will be addressed in future ACTG studies. Modalities being considered for study include the use of antibiotics in late pregnancy and during labor, and cleansing the birth canal with antiseptics to reduce the presence of HlV and other pathogens.
Acquired immune deficiency syndrome vaccine immunotherapy trials in HIV-infected pregnant women are underway to assess the effect of this intervention on vertical transmission. These studies are based on the finding that cell-mediated immune responses appear to correlate with a stable clinical course in HIV-infected patients,30 and as discussed previously, neutralizing antibody may be protective for the infant. Thus, an AIDS vaccine that boosts cell-mediated immunity and broadens the anti-HIV neutralizing antibody repertoire may reduce vertical transmission of HlV.31
A variety of products for passive immunization are being contemplated, including polyclonal human anti-HIV immunoglobulin and monoclonal antibodies. Passive immunotherapies have been used with variable success with other infections, including cytomegalovirus, varicella zoster virus, and hepatitis B. It is hoped an approach similar to that taken to prevent perinatal hepatitis B infection will work with HIV
Active and passive immunization protocols have been developed and are either in progress or will be initiated shortly. Specifically, recombinant envelope protein HIV vaccines are in safety and tolerance (phase 1) trials in HIV-infected pregnant women.
Clinical trials to assess anti-HIV immunoglobulin given to HIV-infected pregnant women with advanced HlV disease will begin shortly to assess whether it will reduce maternal viral load, increase fetal and neonatal passive immunity, and reduce the vertical transmission of HIV.
Studies to examine the mechanisms responsible for perinatal HIV transmission and clinical trials to reduce this transmission are ongoing. A more complete understanding of the timing and modalities of vertical transmission will permit more precise targeting of future clinical trials. Perinatal transmission of HIV infection is most likely due to multiple factors. The degree of viral replication, neutralizing antibody and other maternal immune factors, genetic factors, and an intact placental barrier are most likely important and may be interrelated. Multiple different combination therapies may be necessary to interrupt maternal-fetal HlV transmission.
Pregnancy is a well-defined and limited time period, and offers a model for HlV transmission where clinical, virological, and immunological factors can be evaluated in relation to the occurrence of HIV infection in the infant. The analysis of perinatal trials may provide insight into factors involved in protection and have implications.
As HIV infection rates in the heterosexual populations of US inner cities and in impoverished areas of the third world continue to rise rapidly, strategies are needed urgently to curb the AIDS epidemic in children. Targeting the HIV-infected pregnant woman for therapies is one of the few hopes we have of preventing infection in children at risk of HIV infection. Without such therapeutic strategies, many of these at-risk infants are destined to acquire a chronic viral infection with significant morbidity and mortality.
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