Management of HIV-Exposed Infants
The majority of new human immunodeficiency virus (HIV) infections in children are acquired perinatally, thus emphasizing the importance of effective management of this vulnerable group of infants born to mothers with HIV. Dramatic declines in new childhood HIV infections since 1995 are largely attributable to global efforts to prevent mother-to-child transmission. These efforts include HIV testing, providing antiretroviral treatment (ART) to pregnant and breastfeeding women living with HIV, antiretroviral (ARV) prophylaxis to infants born to mothers with HIV, intrapartum zidovudine when maternal viral load is not suppressed, and cesarean delivery. The recommendations for diagnosis, treatment, and prevention of HIV infection among pregnant women and their infants are constantly evolving, and the most current recommendations can always be found at https://aidsinfo.nih.gov.
KeywordsAcquired immune deficiency syndrome Human immunodeficiency virus Infant Nevirapine Prophylaxis Zidovudine
At the beginning of 2017, approximately 36 million people were living with HIV infection, including approximately 1% of women of childbearing age . Pregnant women with HIV infection can transmit infection to their infant (maternal-to-child transmission [MTCT]). The rate of perinatal transmission of HIV in the absence of any intervention during the prenatal, intrapartum, and postnatal period is approximately 18–32%, where early intervention is crucial in the prevention of perinatal HIV infection . The rate of MTCT has dramatically diminished to less than 2% in the United States and other resource-rich countries, due to the implementation of universal prenatal HIV counseling and testing, maintenance of virologic control in pregnant women with the use of ART, antiretroviral prophylaxis, scheduled cesarean delivery for high-risk pregnancies, and avoidance of breastfeeding [3, 4]. In the United States, where infant formula is widely available and safe, women with HIV are strongly advised to avoid breastfeeding. If an infant is not infected perinatally, the risk of infection from breastfeeding up to 24 months of age by a mother with HIV who is not virologically suppressed approaches 15% . Ultimately, the goal is to minimize perinatal HIV transmission by effectively treating pregnant women with HIV and maintaining their viral load below the limit of detection throughout pregnancy, providing postnatal prophylaxis to all HIV-exposed infants, and avoiding breastfeeding in resource-rich conditions.
Most MTCT of HIV occurs during the perinatal period, due to exposure to infected genital secretions. Perinatally infected infants have viral replication in their lymphoid tissue, including gut and respiratory lymphocytes, before developing viremia . The median time to viremia in perinatally affected infants is approximately 10 days (interquartile range, 6–14 days) . Less commonly, transmission can be congenital if HIV crosses the placenta. Congenital infection has been identified in fetal tissues as early as the first trimester . Congenitally infected infants have positive blood PCR testing in the first 48 h of life . However, there is no difference in the clinical courses of infants infected perinatally versus congenitally.
High viral load during pregnancy
Plasma viral load >1000 copies/mL near the time of delivery
Acute HIV infection
No antepartum or only intrapartum ARV
Known ARV drug-resistant virus
Presence of ulcerative sexually transmitted diseases such as herpes
Prolonged rupture of membranes and prolonged second stage of labor
Use of fetal scalp electrodes, forceps, or other intrapartum devices
Clinical presentations of infants and children with HIV infection (Adapted from )
• Generalized lymphadenopathy
• Recurrent sinopulmonary infection
• Lymphoid interstitial pneumonia
• Leukopenia, anemia, thrombocytopenia
• Invasive bacterial infection, single
• Chronic diarrhea
• Recurrent or unusual viral infection
• AIDS-defining illness (e.g., Pneumocystis pneumonia, disseminated tuberculosis, etc.)
• Multiple or recurrent invasive bacterial infection
Immune category b
No suppression, CD4+ T cells >25% of total lymphocytes
Moderate suppression, CD4+ T cells 15–24% of total lymphocytes
Severe suppression, CD4+ T cells <15% of total lymphocytes
Diagnosis of perinatal HIV infection is largely accomplished by HIV DNA PCR or antibody testing. Other testings, including viral genotyping and phenotyping, resistance testing, and CD4+ T cell testing, are best accomplished by—or in consultation with—an infectious diseases specialist.
Diagnosis and management of HIV-exposed infants
Antibody testing . The detection of HIV-1 antibody is extremely useful in adults; it appears 2–4 weeks after primary HIV infection and stays positive indefinitely. However, anti-HIV antibody is transmitted transplacentally and therefore is not useful for infants age <12 months. A negative antibody test after age 12 months excludes perinatal HIV infection, although maternal antibody may take up to 18 months to disappear. Therefore, positive antibody tests between age 12 and 18 months in an asymptomatic infant should be repeated after 18 months. A positive HIV antibody test beyond age 18 months is consistent with HIV infection [17, 21].
Infants with proven or highly suspected HIV infection should be treated with combination ARV therapy. Therapy should be started immediately rather than waiting for signs of disease or a certain CD4+ T cell level, as prompt therapy is associated with markedly reduced morbidity and mortality . Therapy should include at least three drugs from at least two different antiretroviral drug classes . Many ARV agents, including the commonly used zidovudine and nevirapine, are available as liquid suspensions. Initiation, continuation, and monitoring of ARV therapy should be accomplished with the help of a pediatric infectious diseases specialist or a dedicated HIV treatment clinic.
The fact that the vast majority of HIV-exposed infants are ultimately uninfected is a testament to advances in preventative care over the past 30 years. Prevention recommendations are described below.
Prenatal care . Combination ARV is recommended for all pregnant women, regardless of their CD4+ T cell counts or viral load . ARV reduces maternal viral load in the blood and genital secretions, thus reducing the risk of perinatal transmission [24, 25]. Mothers who are already on an effective regimen should continue that regimen. Women who are not actively being treated with ARV should begin combination therapy guided by virologic resistance testing as soon as possible. Frequent monitoring of viral load is recommended throughout pregnancy and should be assessed again at approximately 34–36 weeks gestation to inform decisions about mode of delivery and infant prophylaxis .
Intrapartum care . The delivery of HIV-infected women is guided by their peripartum viral load. For women whose viral load is undetectable (<50 copies/mL, low risk), no antiviral prophylaxis is needed, and vaginal delivery is appropriate in the absence of other obstetrical indications for cesarean delivery . For women whose viral load is >1000 copies/mL or unknown (high risk), intravenous zidovudine should be given during labor, and a cesarean delivery should be performed [2, 17]. Evidence supports scheduled cesarean delivery at 38 weeks for women with viral load >1000 copies/mL . The optimal management of intermediate-risk women (50–1000 copies/mL) is unclear, but most obstetricians manage these women as though they were high risk . Obstetric procedures that should generally be avoided for high-risk women include artificial rupture of membranes, episiotomy, use of fetal scalp electrodes, and delivery with forceps or a vacuum extractor .
Neonatal dosing of common antiretroviral drugs for prevention or treatment of perinatal HIV infection
Zidovudine (ZDV) prophylaxis
≥35 weeks gestation: 4 mg/kg PO twice daily
>30 to <35 weeks gestation at birth: 2 mg/kg PO twice daily for 2 weeks, then 3 mg/kg PO twice daily for 4 weeks
<30 weeks gestation at birth: 2 mg/kg PO twice daily for 4 weeks, then 3 mg/kg PO twice daily for 2 weeks
Nevirapine (NVP) prophylaxis b
Birth weight 1.5–2 kg: 8 mg dose PO flat dose
Birth weight > 2 kg: 12 mg dose PO flat dose
Three doses in the first week of life:
1. Within 48 h of birth
2. 48 h after first dose
3. 96 h after second dose
5 mg/kg/day (of trimethoprim component) PO either once or divided BID on 3 consecutive days (e.g., Mon/Tue/Wed)
From when zidovudine prophylaxis is complete until HIV infection is excludedc OR 1 year of age, if HIV infected
For certain high-risk scenarios, a three-dose regimen of nevirapine can also be considered. Combination antiretroviral therapy as prophylaxis has received increasing attention due to the “Mississippi baby” experience . In 2010, an extremely high-risk infant (premature, mother with no prenatal care) received prophylaxis with zidovudine, lamivudine, and nevirapine at birth and then transitioned to a treatment regimen of zidovudine, lamivudine, and boosted lopinavir. The child was confirmed to be infected and was treated for approximately 18 months, at which time they were lost to follow up for almost 1 year. When the child reestablished care, the viral load was still undetectable despite the prolonged treatment interruption, raising hope for a “functional cure.” Unfortunately, the child’s viral load became detectable again after approximately 2 years, at which time the child was started on treatment. The prolonged viremia-free period was possibly due to decreased viral reservoirs at the time of infection; studies are investigating this hypothesis in clinical trials . In the meantime, three-drug combination therapy is an option for prophylaxis in high-risk situations .
For infants born to women with known ARV resistance to AZT (or NVP), the optimal prophylactic regimen is unknown and should be determined in consultation with a pediatric HIV specialist or through consultation with the National Perinatal HIV Hotline (888-448-8765) . In addition to ARV prophylaxis, exposed infants should also receive prophylaxis against Pneumocystis jirovecii pneumonia . This is generally accomplished with trimethoprim-sulfamethoxazole prophylaxis beginning at age 4–6 weeks, unless HIV infection has been presumptively excluded by that time. Breastfeeding should be avoided regardless of virologic suppression, unless resources are unavailable for infant formula. In addition, pre-mastication of food should be avoided to prevent postnatal HIV transmission .
- 1.World Health Organization. Global health observatory data. Available at http://www.who.int/gho/hiv/en/. Accessed 13 Feb 2018.
- 3.Centers for Disease Control and Prevention. Enhanced perinatal surveillance—15 areas, 2005–2008. HIV Surveillance Supplemental Report.Google Scholar
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- 19.Caldwell MB, Oxtoby MJ, Simonds RJ, Rogers MF. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Reccomm Rep. 1994;43:1–10.Google Scholar
- 23.U.S. Department of Health and Human Services. AIDSinfo—Guidelines for the use of antiretroviral agents in pediatric HIV infection. https://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0. Accessed 14 Feb 2018.
- 30.U.S. Department of Health and Human Services. AIDSinfo—Guidelines for the prevention and treatment of opportunistic infections in hIV-exposed and HIV-infected children. https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/0. Accessed 14 Feb 2018.