Impact of Neonatal Antiretroviral Therapy
Following the advances in the prevention of maternal-child transmission of HIV that occurred in the United States throughout the 1990's, AIDS cases in children younger than 13 have markedly declined, with almost all of these pediatric cases representing perinatally-acquired HIV infection (Figure 1).[,,] The bulk of this success can be attributed to universal HIV screening during prenatal care combined with the use of antiretroviral therapy during pregnancy and labor. In 1994, the Pediatric AIDS Clinical Trial Group (PACTG) Protocol 076 demonstrated a nearly 70% decrease in the risk of vertical HIV transmission to newborn infants with the use of a three-part zidovudine (Retrovir) regimen that consisted of oral zidovudine initiated at 14 to 34 weeks gestation (antepartum), intravenous zidovudine given during labor (intrapartum), and oral zidovudine administered for 6 weeks to the infant (postpartum). Although this study did not delineate the relative impact of each of the components of the zidovudine regimen, subsequent work has established that most maternal-to-child HIV transmission occurs close to or during the time of labor and delivery. Although the greatest impact on preventing perinatal HIV transmission occurs via sustained maternal viral suppression throughout pregnancy, providing infant antiretroviral prophylaxis can contributes to a reduction in maternal-child HIV transmssion, particularly in situations where the mother did not have fully suppressed HIV RNA levels during pregnancy and the infant starts antiretroviral prophylaxis immediately after birth (Figure 2).
Recommendations for Neonatal Antiretroviral Therapy
The HHS guidelines for interventions to reduced perinatal HIV transmission provides recommendations for infant antiviral prophylaxis, but the specific recommendations depend on the maternal antiretroviral history during pregnancy and whether the HIV RNA was suppressed near delivery. Infant antiretroviral prophylaxis should begin as soon after birth as possible, preferably within 6 to 12 hours. All infants born to an HIV-infected mother should receive a 4 to 6-week course of zidovudine, with or without the addition of other antiretroviral medications—the exact regimen will depend on the mother's antiretroviral history and the most recent HIV RNA level prior to delivery. In the situation where the HIV-infected mother has received standard combination antiretroviral therapy during pregnancy (with consistent suppression of HIV RNA levels and no concerns for maternal adherence late in the pregnancy), a 4-week zidovudine regimen could be considered for the neonate. The 4-week regimen provides the advantage of the infant recovering more rapidly from zidovudine-associated anemia than with the 6-week regimen. In contrast, if the mother has not received combination antiretroviral therapy during pregnancy, the neonate should receive zidovudine for 6 weeks plus three doses of nevirapine (given at birth, 48 hours after the first dose, and 96 hours after the second dose). If the mother has received antiretroviral therapy during pregnancy but has suboptimal viral suppression near delivery, a 6-week zidovudine regimen is recommended and expert consultation (ideally with a pediatric HIV specialist) should be obtained to determine whether the infant should receive a more intensive 2- or 3-drug regimen. The optimal approach for infant postexposure prophylaxis is unkown when the mother has documented or suspected drug-resistant HIV; in this situation, the approach to infant postexposure prophylaxis should be reviewed with a pediatric HIV specialist prior to the delivery. The perinatal guidelines do not recommend routinely using any medications other than zidovudine or nevirapine for neonates, primarily because of lack of data for efficacy, safety, and dosing with other medications. Zidovudine and nevirapine are available in a pediatric formulation; the dose of zidovudine depends on the maternal weeks of gestation at birth and the nevirapine dose is stratified based on the neonatal birth weight (Figure 3).
HIV Testing and Laboratory Monitoring of the Neonate
Because of the transplacental transfer of maternal HIV IgG antibodies into fetal circulation, HIV antibody testing (enzyme-linked immunoabsorbent assay and Western blot analysis) is not useful in the early neonatal period. By the time the child reaches 18 months of age, the maternally acquired HIV IgG antibodies have usually diminished to an undetectable level in the child. Thus, if the child has a positive HIV antibody test after 18 months of age, it generally indicates true HIV infection. In rare instances, children can have a false-negative HIV antibody test, but this usually occurs only in children who have hypogammaglobulinemia. Definitive HIV testing for the infant should employ specific HIV nucleic amplification tests (HIV DNA PCR, HIV RNA PCR, or other related assays).[,,,] The recommendations from the perinatal guidelines state the virologic tests (NATs) should be performed on the infant within the first 14 to 21 days of life, at age 1 to 2 months, and at age 4 to 6 months; a positive test should be confirmed with a repeat test. The diagnosis of HIV in the infant is confirmed if two HIV NATs are positive. Although culture is a highly sensitive test, it is expensive and generally requires at least 2 weeks before results are known. Thus, from a practical standpoint, most clinicians use either the HIV DNA or RNA PCR test. The diagnosis of HIV is presumptively excluded with two or more negative HIV NATs if one is performed at age 14 days and older and the other at age 1 month or older.[,] In infants who do not breastfeed, HIV can be definitively with a negative HIV NAT test at age 1 month or older and another negative test at age 4 months or older. For patients with on-subtype B infection, the HIV NAT can not exclude a diagnosis of HIV infection, since non-subtype B HIV strains are not reliably detected with many of the commercially available HIV NATs. Although many experts recommend using consider two negative HIV antibody tests performed after 12 months of age to rule out HIV infection, some infants have false-positive HIV antibody tests past age 18 months. Additional laboratory testing of infants born to HIV-infected mothers should include a CD4 cell count test at 1 and 3 months of age. Further monitoring of CD4 cell count will be required if the child becomes infected with HIV.
Practices Used for Infant Feeding
In the United States, the perinatal and pediatric guidelines clearly and strongly recommend that HIV-infected mothers should not breastfeed their infants.[,] Although women receiving postpartum combination antiretroviral therapy have significant reductions in cell-free virus in the breast milk, the cell-associated virus is not significantly altered and thus the potential for HIV transmission via breast milk still exists. Mothers and any HIV--infected caregiver should be instructed not to premasticate the infant's food, as case reports have documented HIV transmission via this route.
Prophylaxis for Opportunistic Infections in Neonates
Pneumocystis pneumonia is a potentially fatal condition among children infected with HIV. The 2013 Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children recommends that all infants born to HIV-infected mothers should be considered for prophylaxis for Pneumocystis pneumonia prophylaxis beginning at 4 to 6 weeks after birth. If the infants becomes HIV-infected, prophylaxis for Pneumocystis pneumonia prophylaxis should continue until 1 year of age and then reassessment should be performed at that time. For non-breastfeeding infants who meet presumptive or definitive criteria for not having HIV infection, prophylaxis for Pneumocystis pneumonia is not recommended; early exclusion of HIV infection is possible prior to week 6 with virologic testing of the infant. If HIV RNA testing is not available or is not performed, then the infant should remain on Pneumocystis prophylaxis until 12 months of age. For children with perinatally-acquired HIV, it most often occurs at 3 to 6 months of age, frequently with an abrupt onset, and often with a poor outcome. The infant CD4 count does not factor in the decision to initiate Pneumocystis pneumonia prophylaxis at week 6. Trimethoprim-sulfamethoxazole (Bactrim, Septra) is the preferred drug for Pneumocystis pneumonia prophylaxis; for those infants intolerant of trimethoprim-sulfamethoxazole, acceptable alternatives include dapsone and atovaquone (Mepron) (Figure 4).[,]) Starting prophylaxis in infants younger than 4 weeks of age is not recommended given the very low risk of developing Pneumocystis pneumonia prior to 4 weeks of age and the potential adverse effects with sulfonamides in neonates younger than 4 weeks.
Immunization of Infants Born to HIV-Infected Mothers
Infants born to HIV-infected mothers should receive routine immunizations, although certain precautions exist for use of live vaccines. All infants born to HIV-infected mothers can safely receive standard immunization with DTaP (diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine), rotavirus vaccine, inactivated poliovirus vaccine, Haemophilus influenzae b conjugate vaccine, pneumococcal conjugate vaccine, killed influenza, hepatitis A vaccine, and hepatitis B vaccine. In addition, after 6 months of age, children can receive the killed influenza vaccine. The mumps, measles, rubella (MMR) vaccine and varicella vaccine both use live virus and are contraindicated for women who are severely immunosuppressed (gnerally defined as CD4 percentage less than 15 at any age).
Long-Term Follow-Up of Infants Exposured to Antretroviral Infants
Children born to HIV-infected mothers can incur expousre to antiretroviral medications via transplacental passage while in utero, directly during the infant postpartum postexposure period, or both. Available long-term follow-up data from PACTG 076 have not shown an increase in the risk for neoplasia or organ toxicities among those children who were exposed to the zidovudine regimen when compared with those children who received placebo.[,] Similarly, long-term follow-up of children who received zidovudine have not shown problems with immune function, neurologic development, or growth.[,] The perinatal guidelines recommmend continuing follow-up of infants exposured to antiretroviral medications into adulthood based on the potential carcinogenic effect of the nucleoside reverse transcriptase inhibitors. In addition, the perinatal guidelines recommend that any child exposed to antiretroviral medications who develops a significant organ system abnormality should have evaluation for potential mitochondrial dysfunction.
The National Perinatal HIV Hotline
In some circumstances, optimal management of HIV-infected pregnant women and their infants in an attempt to prevent HIV transmission may benefit from expert consultation. The National Perinatal HIV Hotline (888-448-8765) is a federally funded service providing free clinical consultation for medical providers caring for HIV-infected pregnant women and their infants. The perinatal hotline can also assist with referral to local or regional pediatric HIV specialists.