Human Immunodeficiency Virus Type 1 Infection
The global impact of HIV-1 infection is staggering. The WHO has estimated that, as of the end of 2003, approximately 37.8 million people were living with HIV-1 around the world, two thirds of whom resided in Africa. Approximately 20 million people have died of AIDS since the start of the AIDS pandemic. In 2003 alone, 4.8 million people were newly infected with HIV-1, and 2.9 million others died of AIDS. About 1.1% of all persons between 15 and 49 years of age worldwide are now infected with this virus. In some African countries such as Botswana, 37% of adults are HIV-positive (916).
In the United States, the estimated number of persons diagnosed with AIDS between the start of the epidemic and the end of 2002 is 886,575, of whom 501,669 have died (917). About 950,000 people are currently living with HIV-1 in the United States (916). Females account for 29% of persons 13 years of age or older with HIV-1 infection, 66% of whom are African American and 10% Hispanic (918).
There were between 520,000 and 680,000 HIV-1-infected people living in western Europe at the end of 2003. Since the recognition of AIDS, about 259,000 persons had been diagnosed with this condition as of the end of June 2003, of whom 152,000 had died (919).
The region hardest hit is sub-Saharan Africa where most HIV-1-infected persons are found. The median HIV-1 seroprevalence among women attending antenatal clinics there was about 24% in 2002. The highest rates are found in southern African countries such as Botswana, Lesotho, Zimbabwe, Swaziland, and South Africa (920). South Africa, with a total population of about 44 million people, has 5.3 million HIV-1-infected persons living there (916, 920).
Asian countries such as China, Vietnam, and Indonesia are currently experiencing a growing HIV-1 epidemic, largely driven by sex workers and injecting drug use (921). Estimates place the number of people living with HIV-1 at 570,000 in Thailand, 330,000 in Myanmar, and 220,000 in Vietnam. Imprecise estimates suggest that between 430,000 to 1.5 million Chinese are HIV-infected, and that between 2.2 million to 7.6 million individuals in India are HIV-positive (916).
More than 2 million HIV-infected women around the world give birth each year, and 630,000 infants acquire the virus from their mothers. For 2003 alone, the World Health Organization estimates that about 490,000 children 15 years of age or younger died of AIDS, 90% of whom were from sub-Saharan Africa. AIDS as of the end of 2003 had orphaned at least 12 million children in sub-Saharan Africa (916).
There were 9,300 pediatric (children <13 years of age) AIDS cases diagnosed in the United States through the end of 2002. This accounted for 1% of the 886,575 total AIDS cases reported to the CDC between the start of the epidemic and the end of 2002. Perinatal acquisition of HIV-1 was responsible for 8,629 (93%) of these infections. The major maternal risk factors for perinatal HIV-1 infection were injection drug use (38%), having sex with an injection drug user (17%), sex with an HIV-infected person whose risk status is unspecified (17%), sex with a bisexual male (2%), sex with a person with hemophilia (0.4%), and receipt of blood or blood product transfusions (1.8%). The risk factors are not known for 22% of all mothers of children with AIDS (917). Between 1999 and 2002, heterosexual transmission accounted for 64% of all new HIV-1 infections among females 13 years of age or older; 89% of all heterosexually acquired HIV-1 infections in persons 13 to 19 years of age were female (922).
A disproportionate number of children with perinatal AIDS in the United States have been African American (59%) or Hispanic (23%). White children have accounted for 17% of the cumulative number of cases through 2002. With the success of programs for the interruption of mother-to-infant transmission of HIV-1 and the availability of improved antiretroviral drug regimens for HIV-1-infected children, the number of children diagnosed with AIDS in the United States has steadily declined from 952 in 1992 to a low of 92 in 2002. About 55% of all children 13 years of age or younger diagnosed with AIDS since the start of the epidemic have died (917).
HIV-1 is one of several known human retroviruses. It is a single stranded, enveloped RNA virus that is composed of inner core proteins (p18, p24, p27), surface proteins (gp120, gp41), genomic RNA, and enzymes such as reverse transcriptase and protease. The virion contains three structural genes (gag, pol, and env) and regulatory genes (tat, vif, nef, vpu, vpr, and rev). HIV-1 requires a cell-surface glycoprotein known as CD4 for viral entry into cells. CD4 is found on the subset of T lymphocytes referred to as helper T cells, and on macrophages and other cell types (e.g., placenta, CNS cells). Other cell surface molecules (chemokine receptors) serve as co-receptors for HIV-1 entry into cells. Genetic variants of HIV-1 may preferentially bind to different co-receptors. For example, HIV-1 variants that induce syncytium formation depend on the receptor molecule CXCR4, whereas the nonsyncytium-inducing variants use CCR5 co-receptors. The density of receptors on cells, and the relative densities of co-receptors and CD4 in membrane microdomains, are major determinants of infection (923- 926). The absence of CCR5 in about 1% of Caucasians, as a result of homozygosity for a 32-nucleotide deletion in the coding region (CCR5D32 allele), protects against HIV-1 transmission and delays disease progression (927). Other chemokine receptors such as CCR-2b, CCR-3, and CCR-8 are used by HIV-1 as well (925,928). Patients considered to be long-term non-progressors also tend to have lower amounts of circulating HIV-1 RNA, and their activated CD8 lymphocytes may help suppress viral replication through the release of inhibitory chemokines such as RANTES, MIP-1a, and MIP-1b (925).
Although HIV-1 infects a relatively small number of CD4+ T lymphocytes, there is gradual but massive depletion of these cells over time. This renders patients susceptible to a variety of opportunistic infections and malignancies. Studies have suggested that HIV-1 gp120-induced intracellular activation plays a role in inducing apoptosis of uninfected cells as well (926).
Antibody responses to HIV-1 show only weak neutralizing activities against primary HIV-1 isolates. Most of the antibodies produced are non-neutralizing and directed against virion debris. Neutralizing antibodies do not have much impact on HIV-1 replication, but they do exert immune selection pressure. For control of HIV infection, virus-specific CD8+ cytotoxic T lymphocytes (CTL) are pivotal. These cells can be found in a variety of locations including peripheral blood, spleen, lymph nodes, skin, and bronchoalveolar spaces. CTL lyse HIV-1-infected cells and interfere with virus multiplication. However, HIV-1 replication is error-prone and this allows evasion from virus-specific CTL (929,930).
Major strides have been made in the prevention of perinatal HIV-1 infection in the last decade. The most crucial has been the demonstration that the risk of vertical transmission can be reduced significantly by administration of zidovudine during pregnancy, at delivery, and to newborns (931).
As a result, the CDC recommended use of zidovudine to reduce perinatal transmission of the virus (932). Numerous studies followed and showed the feasibility of using alternative regimens of zidovudine, or of other drugs such as nevirapine, to prevent vertical HIV-1 transmission (933). Use of PCR assays has allowed the diagnosis of HIV-1 infection early in infancy, and the availability of antiviral drugs active at various sites in the viral replication cycle has allowed more potent drug combinations to be administered to infected patients. Viral load monitoring now provides a measure of how successful a therapeutic regimen is in suppressing viral replication for an individual patient, and HIV-1 strains can be examined for mutations associated with resistance to specific antiretroviral agents (934,935,936,937,938).
As a result, the CDC recommended use of zidovudine to reduce perinatal transmission of the virus (932). Numerous studies followed and showed the feasibility of using alternative regimens of zidovudine, or of other drugs such as nevirapine, to prevent vertical HIV-1 transmission (933). Use of PCR assays has allowed the diagnosis of HIV-1 infection early in infancy, and the availability of antiviral drugs active at various sites in the viral replication cycle has allowed more potent drug combinations to be administered to infected patients. Viral load monitoring now provides a measure of how successful a therapeutic regimen is in suppressing viral replication for an individual patient, and HIV-1 strains can be examined for mutations associated with resistance to specific antiretroviral agents (934,935,936,937,938).
Maternal Infection
Epidemiology
Female adults or adolescents have accounted for 18% of all AIDS cases reported to the CDC through 2002. However, the proportion of women among persons newly diagnosed with AIDS has risen to 25% for the years 1998 through 2002. Heterosexual contact with a high risk person was the route of infection for more than half of these women (917). AIDS incidence and deaths have declined since the mid-1990s across all racial and ethnic groups (918). Of women who were living with AIDS at the end of 2002, 59% were African American and 19% were Hispanic (917). HIV-1 seroprevalence among women of child-bearing age varies by state. It ranges from a low of about 0 per 1,000 in Wyoming to highs of 6.9 and 5.2 per 1,000 for the District of Columbia and New York State, respectively. Seroprevalence rates for African American women are 15- to 20-fold higher than for white women, with intermediate rates noted for Hispanic women (939). The risks of HIV-1 infection grow as the number of high-risk behaviors practiced increases. Such behaviors encompass the use of crack cocaine, multiple sexual partners, sexual intercourse with a high-risk partner, having other sexually transmitted diseases, and low level of condom use (940,941,942).
HIV-1 screening programs targeted at patients who acknowledge high-risk behavior generally fail to identify most HIV-1-infected pregnant women (943,944). It is currently recommended that screening be offered to all pregnant women (4). With proper education, the majority of women offered antenatal HIV-1 testing agree to getting screened for this virus (945,946). It has been suggested that in high-risk populations, pregnant women who were initially HIV-1-negative should be screened again during the third trimester (947). However, 15% of HIV-infected women receive no or minimal prenatal care, and another 20% do not seek care until the third trimester (4). Rapid testing for HIV-1 antibodies for women in labor has been evaluated. These tests take about 20 minutes to perform and can provide results within 45 to 120 minutes of blood collection, thus allowing the identification of HIV-1- infected women and instituting intrapartum and postpartum zidovudine prophylaxis (948,949). With nondirective counseling about options for terminating or continuing pregnancy, 85% of HIV-1-infected women elect to continue their pregnancies (943,950).
Many studies have examined the effects of HIV-1 infection on pregnancy outcome, and most have found no significant effects of the virus per se. Adverse pregnancy outcomes were common in a cohort of 634 HIV-1-infected women who delivered after 24 weeks of gestation. These included preterm birth (20%), low birth weight (19%), and small-for-gestational age newborns (24%) (951). Comparable outcomes have been described in other studies, especially those conducted in resource-poor countries (952). With the increased cesarean delivery rates for HIV-infected women, a rise in postpartum and post-cesarean section complications has been observed (952). Maternal HIV-1 infection may increase the rate of spontaneous fetal loss, but this has not been a consistent finding (924, 953,954). Pregnancy itself has a marginal effect, if any, on accelerating the progression of HIV-1 infection in women (924,955-958). In one study of 160 HIV-1-infected women, HIV-1 RNA viral loads did not change significantly during the pregnancy (957).
Mother-to-Infant Transmission
Vertical transmission of HIV-1 can occur in utero, intrapartum, or postpartum (through breast-feeding). Most infants in the United States acquire HIV-1 infection at the time of delivery (959).
Intrauterine transmission accounts for about 30% of all vertically infected infants, and about two thirds of these occur during the last two weeks before delivery (4). Second-trimester fetal blood sampling performed on HIV-1-infected women scheduled for elective pregnancy termination has confirmed the low rate of early in utero HIV-1 fetal infections (960,961).
Many studies have examined maternal and obstetric factors that increase the risk of vertical HIV-1 transmission. Not all risk factors have been consistently identified as such in every study, but there are definite patterns that have been observed. Maternal factors that enhance the risk of HIV-1 transmission to infants include advanced stage of maternal infection, low CD4+ absolute cell count or percentage, elevated CD8+ cell count or percentage, high viral load, p24 antigenemia, illicit drug use, co-infection by other sexually transmitted diseases, low titers or avidity of maternal HIV-1 antibodies, and infection by certain HIV-1 genotypes or phenotypes. Maternal vitamin A deficiency is a risk factor for vertical HIV-1 transmission in developing countries. Obstetric factors favoring HIV-1 vertical transmission include premature delivery, vaginal delivery, cervicovaginal HIV-1 viral load, maternofetal blood transfusions, longer (more than 4 hours) durations of membrane rupture, chorioamnionitis, and use of invasive fetal monitoring devices (959,962-974). Maternal plasma HIV-1 viral load is the strongest single predictor of mother-to-
child transmission (974). For twins born to HIV-1-infected mothers, the first infant delivered, whether vaginally or by cesarean section, appears to be at least twice as likely to be infected as the second-born twin (975). This may be as a result of more intense exposure of the first born to HIV-1-infected genital secretions. de Martino and associates could not confirm these observations in their studies of twins born to HIV-1-infected mothers. They did observe that, if the first-born twin became infected, 42% of their second-born siblings were infected as well. If the first-born twin escaped HIV-1 infection, only 13% of the second-born siblings got infected (976).
child transmission (974). For twins born to HIV-1-infected mothers, the first infant delivered, whether vaginally or by cesarean section, appears to be at least twice as likely to be infected as the second-born twin (975). This may be as a result of more intense exposure of the first born to HIV-1-infected genital secretions. de Martino and associates could not confirm these observations in their studies of twins born to HIV-1-infected mothers. They did observe that, if the first-born twin became infected, 42% of their second-born siblings were infected as well. If the first-born twin escaped HIV-1 infection, only 13% of the second-born siblings got infected (976).
An infant is considered to have early (i.e., in utero) infection if the HIV-1 genome is detected by PCR or if HIV-1 is isolated from blood within 48 hours of birth. Positive results should be confirmed with at least one sample obtained after the neonatal period. An infant is considered to have late (i.e., intrapartum) infection if diagnostic studies (e.g., HIV-1 isolation, PCR, serum p24 antigen assays) are negative in blood samples obtained during the first week of life but become positive during the period from day 7 to 90, and the infant has not been breast-fed. Care should be exercised to avoid contaminating cord blood with maternal blood (977).
In the United States, breast-feeding of infants by infected mothers is not recommended. Postnatal HIV-1 transmission rates by breast-feeding are 8% to 18%, but can be as high as 13% to 39% (mean 26%) when mothers acquire their HIV-1 infection while lactating (978,979). Several factors have been associated with higher rates of transmission through breast milk: RNA viral load in milk or plasma, low maternal CD41 count, breast pathology (mastitis, cracked nipples, abscess), and duration of breast feeding. Because HIV-1 transmission can occur at any time during lactation, longer durations of breast feeding increase the overall risk for HIV-1 infections of infants (979). Both HIV-1-infected cells and cell-free virus are found in breast milk (978,979,980,981). Cell-free virus more commonly is found in mature milk than in colostrum (980). The PCR assay can detect HIV-1 RNA in whole milk or its components (breast milk cells, skim milk, lipid fractions), but the sensitivity appears greatest when whole breast milk is used for testing (981,982). After ingestion of infected breast milk, the virus can be transmitted to the infant through gut mucosal surfaces or tonsillar tissues (979).
In 1998, the WHO recommended that HIV-1-infected women in developing countries be provided information about the benefits and risks of breast-feeding so that they can make an informed decision regarding nutrition for their infants. A study of 371 infants born to HIV-1-infected mothers in Nairobi, Kenya, and randomized to breast- or bottle-feeding revealed comparable two-year mortality rates, even after adjusting for HIV-1 status. Both groups had similar rates of diarrhea or pneumonia during their first two years of life. HIV-1-infected infants had a ninefold higher risk of dying by the age of two years when compared to HIV-1-uninfected infants (983).
Vertical HIV-1 transmission has been reported to occur at various rates in different areas of the world. A report by the 19-center European Collaborative Study provided a rate of 14.4% among a cohort of 721 children followed for 18 months or longer (984). A similar rate of 14% to 20% was observed in a nationwide study of a cohort of 286 children born to HIV-1-positive mothers in Switzerland (985). The rate is about 25% to 30% in the United States for women not receiving zidovudine prophylaxis (931, 986). Rates as high as 50% have been reported from African countries such as Zaire and Kenya (987).
Multiple HIV-1 variants exist in infected persons. These variants arise through errors in reverse transcription and by recombination during retroviral replication. Because of the high turnover rate in the HIV-1 population (more than 10 billion virions are generated daily) and the high error frequency during replication, a large number of variants is produced. These variants subsequently undergo selective pressure from cellular tropism, host immune responses, and antiretroviral therapy. Only a small subset of the HIV-1 variants is transmitted from the mother to her infant, but it can include HIV-1 strains that carry specific drug-resistance mutations (988,989,990,991,992,993). In one study of the first viral isolate from a cohort of 91 HIV-1-infected infants born in New York in 1998 and 1999, 12.1% were shown to harbor zidovudine-resistance mutations (994). There are also concerns that pregnant women with zidovudine resistant HIV-1 strains may transmit the virus more readily to their offspring (993).
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