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Case 4: Discussion

Impact of Neonatal Antiretroviral Therapy

Since the mid 1990's, maternal-child transmission of HIV in the United States has markedly declined[1]. As a result, the number of perinatally-acquired AIDS cases has also dramatic declined (Figure 1)[2]. Most of this success can be attributed to universal HIV counseling and voluntary 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 14-34 weeks gestation (antepartum), intravenous zidovudine given during labor (intrapartum), and oral zidovudine administered for 6 weeks to the infant (postpartum)[3]. Although this study did not delineate the relative importance 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[4].

Currently, it remains unclear whether the third component of PACTG 076--oral zidovudine given for 6 weeks to the newborn--plays a significantly role in reducing maternal-to-child HIV transmission. One epidemiologic study that involved infants whose mothers did not receive antepartum or intrapartum zidovudine failed to show benefit from neonatal zidovudine[5]. In contrast, a retrospective study suggested a benefit in this setting if the neonate started receiving zidovudine shortly after birth (most within 12 hours) (Figure 2)[6]. Data from Africa have demonstrated conflicting results regarding the benefit of short-course neonatal zidovudine when given in addition to single dose neonatal nevirapine (Viramune)[7,8]. Thus, further study is required to better define the impact of neonatal antiretroviral therapy on maternal-to-child HIV transmission and the optimal regimen in this setting.

Recommendations for Neonatal Antiretroviral Therapy

Despite the limitations that exist in our understanding of the benefit of neonatal antiretroviral therapy, the current Public Health Service guidelines recommend that infants born to HIV-infected women should receive a 6-week course of zidovudine, with the recommended dosing for infants born at 35 weeks gestation or later consisting of 2 mg/kg of zidovudine syrup given orally every 6 hours (Figure 3)[1]. The infant should receive the first zidovudine dose as soon as possible after birth, preferably within 6-12 hours. For those infants born at less than 35 weeks gestation (but after 30 weeks) at delivery, the zidovudine (oral or intravenous) should initially be dosed every 12 hours; the zidovudine dose interval should then change to every 8 hours after 2 weeks of age[9]. If the neonate was less than 30 weeks gestation at birth, the dosing interval should change after 4 weeks of age[9]. For HIV-infected mothers with known or suspected zidovudine resistance, some experts would recommend using an alternative to zidovudine, either as monotherapy or combination therapy[10]. Nevertheless, use of drugs other than zidovudine or combination therapy have not been shown to be more beneficial than zidovudine monotherapy in the setting of suspected or known zidovudine resistance. If combination therapy is used in this setting, expert consultation is recommended. Those infants who receive zidovudine should undergo hematologic monitoring consisting of a complete blood count with differential at baseline, at the end of the 6-week course, and, if an earlier value is abnormal, again at 12 weeks. Those infants with anemia at birth should undergo more intensive monitoring. Infants who receive combination antiretroviral therapy should have expanded monitoring that also includes serum chemistries, hepatic transaminase levels, and serum bilirubin levels.

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[11]. In rare instances, children can have a false-negative HIV antibody test, but this usually occurs only in children who have hypogammaglobulinemia[12]. Definitive HIV testing for the infant should employ specific virologic assays (HIV culture, HIV DNA PCR, or HIV RNA PCR)[13,14,15], and a positive test should be confirmed with repeat testing. Direct viral testing, using an HIV PCR assay or culture, should be performed within the first 48 hours after birth, at 1-2 months, and again at 3-6 months of age (Figure 4). A positive test should be confirmed with a repeat test. 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. If the specific virologic test is negative and the infant has no symptoms suggestive of HIV infection, the infant should undergo repeat RNA testing (or culture) at 4-6 months of age. If the HIV tests remain negative at birth, 1-2 months, and after 4 months, the likelihood is greater than 95% that the infant does not have HIV infection. In one study, HIV DNA PCR testing confirmed the diagnosis of neonatal HIV infection in 93% of HIV-infected children at 14 days of age and in 96% on day 28[14]. Infants who have 3 negative PCR tests should then have subsequent monitoring with HIV antibody testing after 12 months of age[11]. Many experts would consider two negative HIV antibody tests performed after 12 months of age sufficient evidence that the child does not have HIV infection. Nevertheless, the National Pediatric Resource Center recommends HIV antibody test at 24 months of age as a final negative confirmatory test. 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.

Prophylaxis for Opportunistic Infections in Neonates

All infants born to HIV-infected mothers should start prophylaxis for Pneumocystis pneumonia 6 weeks after birth (at the time they finish the 6-week course of postnatal antiretroviral therapy) (Figure 5). Several factors have played a role in the rationale for this recommendation. First, when Pneumocystis pneumonia occurs in children with perinatally-acquired HIV, it most often occurs at 3-6 months of age, frequently with an abrupt onset. Second, patients who develop Pneumocystis pneumonia early in life often have a poor outcome[16]. Third, relying on a low CD4 cell count to predict the risk of Pneumocystis pneumonia in young infants is problematic, as shown by studies demonstrating that 10% of children diagnosed with Pneumocystis pneumonia under 12 months of age and 26% under 6 months of age have a CD4 count greater than 1500 cells/mm3[17]. 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 5)[1,18]. Although administering Pneumocystis prophylaxis early in life is recommended, starting prophylaxis in infants less than 4 weeks of age is not recommended given the very low risk of developing Pneumocystis pneumonia prior to 4 weeks of age. Moreover, sulfonamides can cause potential adverse effects, particularly problems secondary to immature bilirubin metabolism and the development of anemia, the risk of which increases when co-administered with zidovudine. Prophylaxis should be discontinued if laboratory testing suggests that HIV infection is unlikely (HIV RNA or cultures negative at 1 month of age or older and again when the infant is 4 months of age or older)[11]. If HIV RNA testing is not available or is not performed, then the infant should remain on Pneumocystis prophylaxis until 12 months of age[11]. If the infant is diagnosed with HIV infection, then Pneumocystis pneumonia prophylaxis should continue.

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 (Figure 6)[18,19]. All infants born to HIV-infected mothers can safely receive standard immunization with DTaP (diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine), inactivated poliovirus vaccine, Haemophilusinfluenzae b conjugate vaccine, pneumococcal seven-valent conjugate vaccine, and hepatitis B vaccine[19]. In addition, after 6 months of age, children can receive the killed influenza vaccine. The mumps, measles, rubella (MMR) vaccine, a live vaccine, is considered safe to give for children with mild to moderate immune suppression (CDC pediatric immune category I or II) (Figure 7). Varicella vaccine, also a live vaccine, is recommended only for those children with minimal immune impairment (CDC pediatric immune category I). Unfortunately, the response to immunizations may be impaired in HIV-infected children.

Long-Term follow up of Infants

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[1,20]. Similarly, long-term follow-up of children who received zidovudine have not shown problems with immune function, neurologic development, or growth[1,20]. Similar long-term follow-up data for children exposed to antiretroviral agents other than zidovudine are inadequate, but studies are ongoing to clarify these long-term safety issues.

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    Figure 1 - Estimated Number of Perinatally Acquired AIDS Cases in United States, by Year of Diagnosis, 1985-2004 Figure 1
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    Figure 2 - Timing of Abbreviated Regimens of Zidovudine (Retrovir) and Risk of Maternal-Child Transmission of HIV Figure 2
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    Figure 3 - Dosing of Zidovudine (Retrovir)* Figure 3
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    Figure 4 - Laboratory Monitoring and Management of Infants Exposed to HIV Figure 4
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    Figure 5 - Primary Prophylaxis for Pneumocystis Pneumonia In Neonates Figure 5
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    Figure 6 -  Recommended Immunization Schedule for HIV-Infected Children* Figure 6
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    Figure 7 - Immunologic categories for HIV-Infected Children, Based on Age-Specific CD4 Counts and CD4 PercentageFigure 7