Chapter 52. HIV-Exposed Neonate and HIV At-Risk Child

Worldwide, more than 2 million children younger than 15 years are infected with HIV, with perinatal transmission the source of most of these infections.1,2 In the developed world, where prenatal testing and safe and effective antiretroviral prophylaxis are widely available, perinatally-acquired HIV has become almost entirely preventable. With early testing and treatment of HIV-infected mothers and their newborns the risk of perinatal HIV transmission can be reduced to less than 2%.3 The pediatric provider plays an essential role in disease reduction. By early identification of HIV-exposed infants, timely virologic testing and provision of postpartum HIV and opportunistic infection prophylaxis, pediatric care providers can intervene to dramatically reduce the risk of infection for the neonate.

Perinatal transmission of HIV denotes infections that are acquired during the intrauterine, intrapartum and postpartum periods. In the United States, the peak years of perinatal HIV transmission occurred in the early 1990s, with 1650 new infections diagnosed in 1991 alone.4 In recent years there has been a dramatic reduction in new HIV infections, with a 95% reduction in the incidence of perinatally acquired HIV from 1992 to 2004 in the United States.4 In 2002, an estimated 144–236 new perinatal HIV infections were diagnosed in the United States.4 These cases represent those women who either refused or were not offered prenatal HIV testing, had suboptimal antiretroviral adherence during pregnancy, presented at term without prenatal care, or experienced rare unexplained treatment failures.

The reduction in new infections in the developed world is a direct consequence of perinatal antiretroviral regimens. In 1994, the Pediatric AIDS Clinical Trials Group released the results of their landmark 076 study, examining the effect of a three-part regimen containing the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (ZDV). The active treatment arm consisted of maternal oral ZDV therapy beginning at 14–34 weeks gestation, intravenous ZDV in labor, and infant oral ZDV for 6 weeks. The HIV infection rate in the ZDV-treated group was 8% at 18 months versus 26% in placebo group—a remarkable 68% reduction in HIV transmission.5 Based on the study findings, in 1994 the Centers for Disease Control and Prevention and U.S. Public Health Service issued recommendations for the routine use of the three-part ZDV regimen for all pregnant HIV-infected women.6

In July 1995, the U.S. Public Health Service issued recommendations for universal prenatal HIV counseling and consensual testing.7 In 2006, the Centers for Disease Control and Prevention revised its HIV testing recommendations to increase early detection of HIV in pregnancy. The new guidelines focus on implementing HIV screening as a routine part of prenatal care, rather than as an optional test. As such, they recommend “opt-out” testing, whereby all women should receive the test as part of their care unless they specifically decline. The Centers for Disease Control and Prevention also recommends a second screening in the third trimester for women with known risk factors or those in high prevalence areas (as defined by an incidence of at least one HIV infection per thousand pregnant women).8 Early diagnosis of pregnant women is critical for timely implementation of the recommended antiretroviral prophylaxis regimen to the mother and infant dyad.

In the absence of peripartum antiretroviral prophylaxis, rates of HIV transmission range from 14% to 35% in the developed world.4,9 In the developing world, where prolonged breast-feeding is the norm and maternal HIV infection is often poorly controlled, transmission rates range from 25% to 48%.10 With an optimized regimen of prenatal care and maternal highly active antiretroviral therapy (HAART) as well as intrapartum and postnatal ZDV prophylaxis, perinatal transmission rates are reduced to as low as 1%.3

Understanding the timing of perinatal HIV infection is a key step toward meaningful implementation of the perinatal prophylaxis recommendations. While it was initially believed that the majority of perinatal HIV infections occurred in utero, most transmission in fact occurs during the intrapartum period with in utero transmission accounting for less than 10% of all perinatal HIV infections.11 Postpartum infection is largely caused by breast-feeding. A meta-analysis of prospective cohort studies estimated the risk of transmission of HIV-1 through breast-feeding as 16%.12 The risk increases with longer duration of breast-feeding, high maternal viral load, the presence of mastitis and mixed formula and breastmilk feeding.13

The three-part antiretroviral regimen for prevention of mother- to -child transmission (PMTCT), based on the Pediatric AIDS Clinical Trials Group 076 ZDV-centered regimen, is constructed to prevent HIV transmission at all possible time-points.3,6

While alternate PMTCT regimens have been studied, the ZDV-based regimen is considered the gold-standard treatment. However, maternal monotherapy with ZDV is now believed to be suboptimal, and maternal ZDV-based HAART is warranted for all pregnant HIV-infected women in regions where combination antiretroviral therapy is available.3,14 HAART is defined as a combination regimen of at least three drugs, from two different classes of anti-HIV agents. If an alternative prophylactic regimen must be considered, providers should consult the U.S. Public Health Service Task Force perinatal treatment guidelines, available at www.aidsinfo.nih.gov/Guidelines to obtain the most up-to-date information on perinatal prophylaxis and PMTCT regimens.3

Maternal antiretroviral therapy inhibits in utero infection, while intravenous ZDV in labor acts as preexposure prophylaxis against intrapartum infection.3 As intrapartum and postpartum ZDV add additional mechanisms of protection against transmission, all HIV-infected women should receive intravenous ZDV in labor, even if they have received HAART during pregnancy. If only intrapartum and oral infant ZDV are given, transmission rates still decrease from 27% to 10%.15 In resource-poor settings where access to prenatal care and antiretrovirals is limited, a simplified regimen consisting of a single intrapartum dose of the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) followed by a single infant dose at 48–72 hours of life may be used. This regimen has been shown to reduce HIV transmission in a breast-fed population to 16% at 18 months of age compared to a 26% transmission rate in patients receiving an abbreviated regimen of oral intrapartum and neonatal ZDV16,17 However, recent data indicate that this intervention may induce maternal and infant NVP resistance and decrease later virologic response to NNRTI-based therapy.18 The mode of delivery also has a significant impact on the risk of transmission in the setting of poorly controlled maternal HIV infection. A meta-analysis of prospective cohort studies examining the impact of cesarean section found a 50% reduction in HIV transmission associated with cesarean delivery, independent of antiretroviral therapy.19 Current guidelines recommend planned cesarean delivery at 38 weeks for HIV-1-infected women with viral loads greater than 1000 copies/mL near term.20

In the postnatal period, infant ZDV functions as postexposure prophylaxis. In the absence of prenatal or intrapartum prophylaxis, infant ZDV should still be implemented as soon as possible after birth. The initiation of infant ZDV only as postexposure prophylaxis has reduced infection rates from 27% to 9% if initiated in the first 2 days of life.15 Starting ZDV prophylaxis after 48 hours has not been shown to reduce HIV transmission.3

In regions of the world where clean water and infant formula are widely available, the risk of postnatal transmission is further reduced by avoidance of breast-feeding. However, in resource-poor settings where excess infant morbidity and mortality have been associated with the use of infant formula, particularly where access to potable water is limited and formula use is hampered by cost and social stigma, HIV-infected women should continue breast-feeding.21,22 Mixed formula and breastfeeding has been associated with an increased risk of HIV infection, and should be avoided. In resource-poor settings, HIV-infected women have been advised to exclusively breast-feed for the first 4–6 months of life, followed by rapid weaning.13 However, recent data suggest that early weaning does not lower the risk of infection, and may increase mortality.23 While HIV-infected women in developing nations should continue to exclusively breast-feed, the optimal time for weaning is yet to be determined.

There are no signs and symptoms that reliably indicate neonatal HIV infection. As such, any initial assessment of an infant with potential HIV exposure includes a thorough history detailing the prenatal course and intrapartum events. The role of the pediatric provider in the immediate postpartum period is not only to implement testing and infant prophylaxis, but also to assess the risk of infant infection. Maternal factors including high maternal plasma viral RNA level (viral load) at delivery, advanced HIV disease and the absence of HAART during pregnancy are associated with an increased risk of transmission.9 In addition, intrapartum factors including vaginal delivery, rupture of membranes for greater than 8 hours, and preterm delivery also increase the risk. Evidence suggests that cigarette smoking, chorioamnionitis, other active sexually transmitted infections and invasive intrapartum procedures such as fetal scalp monitoring and episiotomy may also increase HIV transmission.11

An important role of the pediatrician is to assess the HIV status of all patients, regardless of age, race or socioeconomic status. Patients for whom maternal HIV serostatus is not known, as well as infants and children in substitute care, should undergo routine HIV testing. There are a number of clinical presentations and medical conditions, described in Table 52–1, which should raise provider suspicion of HIV infection and warrant testing. If suspicion of HIV is high in such cases, prophylaxis against Pneumocystis jiroveci pneumonia (PCP) should be implemented, pending receipt of test results.

While HIV may be the parent and provider's primary concern, pediatricians must be cognizant of the possibility of other perinatal infections which exhibit a high comorbidity with HIV, such as hepatitis B and C, syphilis, toxoplasmosis, cytomegalovirus, herpes simplex virus and tuberculosis.24 As these conditions have a significant impact on the health of the neonate, maternal health screening and neonatal examination must also focus on these conditions.

Primary immunodeficiency diseases, particularly T-lymphocyte defects or combined B- and T-lymphocyte defects, may mimic the clinical presentation of children with the acquired immunodeficiency syndrome. Important T-lymphocyte defects include 22q deletion (DiGeorge Syndrome) and lymphocyte activation defects. Children with combined B- and T-lymphocyte defects, such as severe combined immunodeficiency syndrome, may present with PCP and other opportunistic infections commonly seen in HIV-infected children.

The diagnostic and treatment algorithm for the HIV-exposed infant is detailed in Figure 52–1. The most important first step for prevention of perinatal HIV infection is timely prenatal screening of all pregnant women. Knowledge of maternal serostatus allows for rapid implementation of perinatal prophylaxis and postpartum testing for the neonate. In cases where there has been no prenatal care or maternal HIV testing, maternal serostatus may be unknown at the onset of labor. In these scenarios, intrapartum HIV testing with maternal consent via expedited enzyme immunoassay (EIA) or rapid-testing kit may allow for expedient administration of intravenous ZDV prior to delivery.25,26 Several rapid-testing kits are currently licensed for use in the United States.25 The Mother-Infant Rapid Intervention at Delivery trial of HIV rapid testing in labor found the test to be 100% sensitive and 99.9% specific, with results available within 65 minutes.26 Positive rapid tests must be confirmed with a separate HIV EIA or western blot assay.25 However, empiric intrapartum ZDV and oral infant ZDV should be implemented immediately following an initial positive EIA, and should not be delayed while confirmatory results are pending.

In cases where maternal serostatus has not been confirmed prior to delivery, the pediatrician's role is to determine the neonate's HIV-exposure status as soon as possible with expedited HIV EIA or rapid testing of the infant.27 Owing to the placental transfer of maternal IgG in the third trimester, virtually all HIV-exposed infants will have a positive EIA at birth. A positive HIV EIA before 18 months of age indicates HIV-exposure, but cannot diagnose infection. As with maternal testing, any positive EIA or rapid test results must be confirmed by a supplemental EIA and western blot.24 With confirmation of exposure, it is essential to initiate infant antiretroviral prophylaxis as soon as possible. If EIA results are unavailable during this period, the pediatrician should consider initiating ZDV pending test results when the pretest probability of infection is high. Procedures for obtaining documented maternal consent for infant HIV testing vary by state, and physicians should be familiar with the consent laws of their region. For infants and children in substitute care, state child welfare agencies may be able to provide consent depending on state and local law. In circumstances where the suspicion of HIV is high and parental consent has been refused, a court order may be necessary to perform HIV testing.

Virologic specific tests such as the HIV DNA polymerase chain reaction (PCR) assay or HIV culture are needed to definitively diagnose HIV infection in the neonate. The revised testing schedule recommends an initial virologic test drawn at 2–3 weeks of life, followed by a second test at 1–2 months, and a final virologic test between 4–5 months of life.14 State guidelines may vary with respect to the specific timing of infant HIV testing, and pediatric providers should be familiar with regional practices. Many sites draw a first virologic test at day one or two of life. Testing at 48 hours of life allows for early implementation of optimal therapy should the test indicate infection.27 A positive virologic test at or before 48 hours indicates in utero infection, whereas a negative virologic test in the first week of life followed by a subsequent positive test after 2 weeks suggests intrapartum infection.14 While early neonatal testing is essential, up to 60% of HIV-infected infants will have negative test results at 48 hours of life. While a positive test strongly indicates infection, a negative test in this early period does not exclude the possibility of HIV transmission.14

The standard virologic test in infancy is the HIV DNA PCR assay.28 This qualitative test gives a “yes, HIV was detected” or “no, HIV was not detected” answer. It indicates either the presence or absence of HIV DNA in peripheral blood mononuclear cells, but does not quantify the number of detectable copies. Sensitivity of the test is 40% within the first 2 weeks of life, but increases to 93% by 14 days. By 1 month of life, the test is 96% sensitive and 99% specific in identifying HIV.14 Cord blood should not be used in postpartum testing, as it may contain maternal blood cells resulting in a false positive assay.24 The sensitivity of the currently available HIV-1 DNA PCR assays are reduced for non-B subtypes of HIV. While the B subtype of HIV is predominant in the United States, there is extensive global variation in HIV subtypes and clades. In cases where maternal infection with a non-B subtype is known or suspected, the infant should be tested for HIV with a branched-chain DNA (bDNA) test of HIV culture as well as the standard DNA PCR.29

Quantitative HIV RNA PCR assay, the test typically used to evaluate viral load in confirmed HIV infection, has a sensitivity comparable to the DNA test, but a higher false positive rate. Although minor, this decrease in specificity limits its utility as the primary test for HIV-exposed infants.30 However, infant viral load is highly correlated with disease progression, making RNA PCR assay an excellent confirmatory test for a positive DNA PCR assay. Finally, HIV-1 peripheral blood cell culture is considered the gold standard for the detection of HIV infection. Its sensitivity is equal to that of the HIV DNA PCR and it is 100% specific. However, its use is often limited by its significant expense, limited availability and long (up to 28 days) turn-around time for results.24 In facilities where HIV culture is available, it may be used in tandem with the DNA PCR assay at 1 month to assess infection. All positive virologic tests must be confirmed by a second test on a separate sample. Infection is defined by at least two positive virologic tests drawn at different times.

HIV infection can be excluded with some confidence in a non–breast-fed; 5-month-old infant who has had at least two negative virologic tests provided these tests occurred at least 1 month and 4 months after birth.14 In infants who are presumed to be uninfected by virologic testing, serologic testing by HIV EIA should be performed at 1 year to confirm the disappearance of maternal anti-HIV IgG. If the EIA remains positive, the test should be repeated between 15 and 18 months.14,24 While in rare cases, HIV-uninfected children may retain maternal antibodies after 18 months, it is generally accepted that a confirmed positive EIA after ≥18 months of age indicates HIV infection. Virologic testing should be repeated in this instance.14,24 For children older than 2 years, initial testing may be done using the HIV EIA. Infection is confirmed by 2 positive HIV antibody tests (each with confirmatory western blots), drawn on different days. HIV RNA PCR should follow to quantify viral load.

In resource poor areas, the feasibility of repeated testing is often limited. Numerous ongoing trials aim to identify cost-effective and accurate diagnostic algorithms. HIV EIA testing at 6 weeks, which is relatively cheap and widely available, may be used to identify HIV-exposed infants. EIA samples may be saved as dried blood spots on filter paper, and sent to the nearest comprehensive laboratory facility for PCR confirmation. CD4+ cell count at 1 and 3 months may be used as another surrogate marker for infection, although the specificity of this method is poor.

The HIV-exposed neonate should be assessed in the immediate postpartum period, and then followed in the outpatient setting at 1 week, 1 month, and 2, 4, 6, 9, 12 months. Virologic testing should be performed at the 1- and 4-month visits, and serologic testing should commence at 12 months. All routine immunizations should be given to HIV-exposed infants, with the exception of the recently approved rotavirus vaccine.24 As this vaccine is not yet approved in HIV-infected children, it should be omitted from the immunization schedule until HIV infection has been reliably excluded. If HIV infection is confirmed, immunization guidelines for HIV infected children should be followed.

Treatment of the HIV-exposed neonate begins with implementation of ZDV therapy in the immediate postpartum period. In cases where risk of infection is high, that is, failure to implement prenatal or intrapartum prophylaxis or known maternal nonadherence to HAART, clinicians may consider adding a second antiretroviral to the infant regimen. The antiretrovirals of choice in these scenarios are those for which infant dosing is well established—the NRTI lamivudine 2′,3′-dideoxy-3′-thiacytidine (3TC) and/or the NNRTI NVP. However, evidence to support this treatment approach is limited, and such complicated cases should be managed in consultation with a specialist in pediatric HIV. Antiretroviral dosing for preterm and full-term infants is detailed in Table 52–2.

After discharge from the hospital, the infant and primary caregiver should be seen for a full outpatient assessment at 1 week of life. Comprehensive management of the HIV-exposed neonate includes a thorough review of maternal health information in order to garner information about the perinatal course and assess the risk of infant infection with HIV and other related pathogens. Counseling should be provided to the primary caregivers regarding the duration of therapy, testing schedule, and the importance of avoiding breast-feeding to prevent late postnatal transmission. As the mother may be recently diagnosed, referral to support services and HIV treatment is an essential aspect of family-oriented care. In addition, all siblings of the infant should undergo HIV testing, following the testing schema detailed above, if their serostatus is unknown, regardless of their age.24 One of the primary roles of the pediatrician is to monitor infant ZDV therapy during the 6-week prophylactic regimen. Antiretroviral adherence and adverse effects should be assessed at each encounter. The most common adverse effect associated with neonatal ZDV treatment is a mild, macrocytic anemia that generally resolves after 2 months.28,31 Neutrophil, lymphocyte and platelet counts may also decrease.31 A complete blood count with differential should be performed at birth, 2 weeks, and 4 months to monitor any changes in hematologic parameters.24

The potential toxicity of ZDV has been a topic of some debate. As an inhibitor of DNA polymerase gamma, ZDV is known to act as a human mitochondrial toxin. Large cohorts of ZDV-treated HIV-exposed infants in the United States have failed to find any cases of mitochondrial toxicity.32 However, 12 cases of confirmed, and 14 cases of possible, mitochondrial toxicity have been reported within a French cohort of ZDV-treated infants. Neurologic signs of mitochondrial toxicity included encephalopathy, seizures, and developmental delay. The overall incidence of mitochondrial toxicity in this cohort was 0.26%, with findings occurring more commonly in infants treated with a combination of ZDV and the NRTI lamivudine (3TC).33 Because of this potential risk, ZDV and/or 3TC-treated infants should receive a thorough neurologic examination at all routine visits. While maternal prenatal ZDV treatment has not been associated with an increased risk of congenital anomalies,34 less information is available about the risks of in utero exposure to the various other antiretroviral components of HAART. Efavirenz is a known teratogen, and infants exposed to this NNRTI are at risk for congenital anomalies. All infants with in utero exposure to HAART should be assessed for congenital anomalies at birth, 6 months, and yearly thereafter.3,24 Any instances of suspected adverse effects or congenital anomalies related to antiretroviral exposure should be reported the Antiretroviral Pregnancy Registry.35 Ongoing trials examining long-term outcomes of uninfected ZDV-treated and HAART-exposed infants are underway in the hopes of resolving these questions.

At 6 weeks of age ZDV prophylaxis should be discontinued provided the infant has had two negative DNA PCRs, with one drawn at 2 weeks of life, and the second after 4 weeks of life. In such cases, HIV infection is presumptively excluded and prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) does not need to be initiated. In the era prior to routine prophylaxis, PCP was the most common opportunistic infection in HIV-infected children. Disease incidence peaks at 3–6 months of age and tends toward an acute and severe course. Unlike many other opportunistic infections, PCP may occur at relatively high CD4+ cell counts.28 As it is difficult both to ascertain which HIV-infected infants are at risk for PCP and to confirm HIV-infection during the period of peak incidence, trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis is recommended for HIV-exposed infants of indeterminate status and all HIV-infected infants starting at 4–6 weeks of age regardless of their CD4+ cell count.36 TMP/SMX prophylaxis should generally be delayed until 6 weeks to avoid both the additive hematologic marrow suppression effects of combined ZDV and TMP/SMX prophylaxis, and the concern for neonatal hyperbilirubinemia associated with early administration of sulfa antibiotics. Prophylaxis with TMP/SMX is continued until a second negative virologic test is available at 4 months of age. If virologic test results are unavailable or if the infant is found to be HIV-infected, TMP/SMX prophylaxis should be continued until a minimum of 1 year of age. The incidence of PCP decreases dramatically after the first year of life, and only those HIV-infected children with a past history of PCP or CD4+ cell counts suggesting severe immunosuppression should remain on prophylaxis past 1 year of age. In the case of sulfa allergy, oral atovaquone or dapsone therapy may be used. Monthly intravenous pentamidine is another option for PCP prophylaxis, however, the cumbersome route of delivery makes it a less feasible option for HIV-exposed children and their families. Dosing schedules for TMP/SMX and alternative regimens are detailed in Table 52–3.

Comprehensive care of the HIV-infected mother and the HIV-exposed infant have dramatically lowered the rate of new perinatal HIV infections. Virtually, all perinatal HIV infections in the developed world are now preventable through antiretroviral prophylaxis. Great strides are still to be made in sub-Saharan Africa and other HIV-endemic regions of the world where over 1500 new pediatric infections occur everyday.2 Globally, the increased availability of PMTCT programs, combined with educational interventions to produce sustainable changes in risk behavior, will be key to improving the outcomes of all children with perinatal HIV exposure.

1. All infants should undergo rapid HIV testing if maternal HIV serostatus is unknown.

2. ZDV should be initiated as soon as possible and not later than 48 hours for all infants with known perinatal HIV exposure.

3. Virologic testing of the HIV-exposed neonate by DNA PCR should be performed at birth, 1 and 4 months of age, and serologic testing by HIV EIA should commence at 12 months.

4. A positive HIV EIA before 18 months of age confirms HIV exposure, not infection, and virologic testing such as DNA or RNA PCR is needed to confirm infection.

5. A positive HIV EIA after 18 months of age suggests infection and requires immediate confirmation with a second HIV EIA and western blot.