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Management of HIV-Exposed Infants

  • Wei Li A. Koay
  • Allison L. Agwu
Chapter

Abstract

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.

Keywords

Acquired immune deficiency syndrome Human immunodeficiency virus Infant Nevirapine Prophylaxis Zidovudine 

Epidemiology

At the beginning of 2017, approximately 36 million people were living with HIV infection, including approximately 1% of women of childbearing age [1]. 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 [2]. 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% [5]. 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.

Pathogenesis

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 [6]. The median time to viremia in perinatally affected infants is approximately 10 days (interquartile range, 6–14 days) [7]. 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 [8]. Congenitally infected infants have positive blood PCR testing in the first 48 h of life [9]. However, there is no difference in the clinical courses of infants infected perinatally versus congenitally.

Several factors contribute to a high risk of MTCT, including:
  • 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

All of these risk factors increase either the amount of virus present in blood and genital fluid or the amount of time the infant is exposed to virus [10, 11, 12, 13, 14, 15, 16].

Clinical Findings

The majority of HIV-exposed infants are ultimately found to be uninfected. However, infants who are HIV-infected perinatally are initially asymptomatic, and therefore all HIV-exposed infants must receive prophylaxis and virologic follow-up to ensure that infected children are not missed (see Prevention, below) [17]. Infants who are infected with HIV can present in a variety of ways (Table 1) [18]. Most commonly, the infants do not yet have clinical signs when virologic testing becomes positive. Other infants may present with failure to thrive or growth delays. Diffuse lymphadenopathy, including hepatosplenomegaly as well as cervical and inguinal adenopathy, is a common but nonspecific presentation of perinatal HIV. Severe or persistent candida rash, chronic seborrhea, chronic diarrhea, and recurrent sinopulmonary infections (e.g., otitis media, sinusitis, pneumonia) are also common presenting signs but may be difficult to differentiate from normal childhood infections initially. As infections get more severe, clinical suspicion for HIV infection should increase. Invasive bacterial infections, recurrent viral infections, persistent or unexplained anemia, leukopenia, or thrombocytopenia, and the like should raise concerns, particularly if growth failure or adenopathy is present. Any AIDS-defining lesion—most commonly Pneumocystis pneumonia—should prompt immediate testing and treatment [19].
Table 1

Clinical presentations of infants and children with HIV infection (Adapted from [19])

Clinical category

N

Asymptomatic

A

Mildly symptomatic

 • Generalized lymphadenopathy

 • Hepatosplenomegaly

 • Recurrent sinopulmonary infection

 • Dermatitis

 • Parotitis

B

Moderately symptomatica

 • Lymphoid interstitial pneumonia

 • Leukopenia, anemia, thrombocytopenia

 • Invasive bacterial infection, single

 • Chronic diarrhea

 • Recurrent or unusual viral infection

C

Severely symptomatic

 • AIDS-defining illness (e.g., Pneumocystis pneumonia, disseminated tuberculosis, etc.)

 • Multiple or recurrent invasive bacterial infection

Immune category b

1

No suppression, CD4+ T cells >25% of total lymphocytes

2

Moderate suppression, CD4+ T cells 15–24% of total lymphocytes

3

Severe suppression, CD4+ T cells <15% of total lymphocytes

aPartial list

bPercentages used rather than absolute CD4+ T cell count due to relatively higher total lymphocyte count in infants and young children (e.g., a child with 14% CD4+ T cells may have a CD4+ count of 1100 but still be considered severely immunosuppressed)

Diagnosis

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.

HIV DNA PCR. PCR is >95% sensitive and specific for perinatal HIV infection after 1 week of age [20]. As mentioned above, infants who are perinatally infected (rather than congenitally) may have a falsely negative 48 h DNA PCR because the virus is still limited to their mucosal lymphocytes at that point and has not yet reached the blood. Therefore, DNA PCR testing is ordered several times during early infancy (Table 2). HIV RNA PCR is not routinely used, as RNA PCR can be falsely positive if it detects maternal virus that is coating the infant’s skin but not replicating. In contrast, DNA PCR identifies active, replicating virus that has already undergone reverse transcription and therefore is a more specific test. However, any positive PCR should be promptly repeated, since false positives occur with any assay [21].
Table 2

Diagnosis and management of HIV-exposed infants

Black bars or Xs indicate recommended management. Gray bars indicate optional situations

TMP-SMX, trimethoprim-sulfamethoxazole

aZidovudine should be given for 4 or 6 weeks as per Table 3

bNevirapine should be given in high-risk situations as per Table 3

cTMP-SMX should be given once zidovudine prophylaxis ends if HIV not already presumably excluded (two negative DNA PCR tests, at least one of which was obtained at age ≥ 4 weeks

dComplete blood counts before beginning zidovudine and then monthly; can be continued if antiretroviral therapy continues beyond 6 weeks

eAntibody test may be obtained as early as age 12 months; a negative test after age 12 months definitely excludes infection, but a positive test between 12–18 months should be repeated after age 18 months. A positive antibody test after age 18 months is consistent with infection

fImmunizations should be given as per usual childhood schedule for HIV-exposed and HIV-positive infants, including rotavirus. The only exceptions are that measles-mumps-rubella and varicella-zoster vaccine should not be given to HIV-positive children whose CD4+ T cell percentage is <15% and that live attenuated influenza vaccine is contraindicated for HIV-positive children

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].

Treatment

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 [22]. Therapy should include at least three drugs from at least two different antiretroviral drug classes [23]. 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.

Prevention

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 [17]. 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 [17].

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 [17]. 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 [26]. 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 [27]. 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 [17].

Infant care . After delivery, all HIV-exposed infants should receive postpartum antiretroviral drugs as soon as possible (no later than age 6–12 h) to minimize the risk of perinatal HIV transmission (Table 3) [17]. Zidovudine is the primary agent and should be used for a minimum of 4–6 weeks pending results of the infant’s virologic testing. Six weeks was the traditional duration, but recent evidence supports limiting zidovudine to 4 weeks if the mother’s viral load was undetectable at the time of delivery.
Table 3

Neonatal dosing of common antiretroviral drugs for prevention or treatment of perinatal HIV infection

Drug prophylaxis

Dosing

Duration

Zidovudine (ZDV) prophylaxis

≥35 weeks gestation: 4 mg/kg PO twice daily

4–6 weeksa

>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

Trimethoprim-sulfamethoxazole

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

aFor infants whose mothers had antenatal therapy and undetectable viral load at the time of delivery, only 4 weeks of zidovudine are indicated

bNevirapine should be added to zidovudine for infants born to mothers who (1) have not received any antepartum therapy, (2) had primary (acute) HIV infection during pregnancy, or (3) were treated but did not achieve undetectable viral load before delivery, particularly if delivery was vaginal

cIf HIV infection is presumptively excluded before end of zidovudine therapy (e.g., 1-week and 4-week HIV DNA PCRs are negative and 6-week course of zidovudine is completed), then trimethoprim-sulfamethoxazole prophylaxis is not necessary

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 [28]. 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 [29]. In the meantime, three-drug combination therapy is an option for prophylaxis in high-risk situations [17].

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) [17]. In addition to ARV prophylaxis, exposed infants should also receive prophylaxis against Pneumocystis jirovecii pneumonia [30]. 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 [31].

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Infectious Diseases, Department of PediatricsJohns Hopkins UniversityBaltimoreUSA

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