Posted January 2014
All HIV-exposed infants should receive care from, or in consultation with, a pediatrician experienced with HIV treatment and management. (AI)
The pediatric HIV epidemic has changed dramatically in New York State since the late 1980s, largely as a result of earlier diagnosis of HIV infection in pregnant women and antiretroviral (ARV) prophylaxis to prevent mother-to-child transmission (MTCT) of HIV. In 2012, the rate of MTCT in New York State was only 0.8% (3 cases). Although there has been a significant decline in MTCT, New York State continues to have approximately 450 to 500 HIV-exposed infants born annually. Pediatricians play an important role in ensuring the health of these HIV-exposed infants by providing HIV-related follow-up care that includes neonatal ARV prophylaxis, serial diagnostic testing to determine HIV status, and counseling to the mother regarding avoidance of breastfeeding.
In New York State, if a woman’s HIV status is unknown when she presents for delivery (i.e., no documentation of a negative HIV test during the current pregnancy and she is not known to be HIV-infected), expedited HIV testing must be conducted. New York State requires that results of expedited HIV testing in the obstetrical setting must be available as soon as possible, preferably within 1 hour, and no longer than 12 hours after the mother’s consent or the infant’s birth if the mother declines testing.
For purposes of this chapter, an exposed infant is any infant born to a mother with HIV infection.
I. NEWBORN ANTIRETROVIRAL PROPHYLAXIS FOR HIV-EXPOSED INFANTS
Clinicians should administer zidovudine (ZDV) for prevention of mother-to-child-transmission of HIV to all HIV-exposed infants as soon as possible after birth (AI):
- ZDV (4mg/kg PO twice daily) should be administered as soon as possible after birth, within 6 hours, and no later than 12 hours of delivery (AII)
- ZDV prophylaxis should be given for 6 weeks (AI); dose adjustments should be made as the infant’s weight changes
- Dosing of ZDV prophylaxis should be adjusted for premature infants <35 weeks’ gestational age (see Table 1) (AII)
Clinicians should administer supplemental ARV prophylaxis as close to the time of birth as possible for the following infants:
- Infants born to HIV-infected women who received no antepartum antiretroviral therapy (ART) and only intrapartum ZDV
- Infants born to HIV-infected women who received no antepartum ART and no intrapartum ZDV
- Infants born to HIV-infected women with suboptimal viral load levels (>1,000 copies/mL) (consider)
- Infants born to HIV-infected women with known drug-resistant HIV
The preferred prophylactic regimen includes 6 weeks of daily ZDV plus 3 doses of nevirapine administered during the first week of life (at birth, 48 hours after the first dose, and 96 hours after the second dose). See Table 1 for dosing. (AI)
Clinicians should consult a pediatric provider who has experience with HIV treatment and management when using combination regimens other than those shown in Table 1 and should discuss potential risks and benefits with the mother. Whenever possible, consultation should occur before delivery. Clinicians who do not have access to experienced pediatric HIV clinicians should call the New York State Pediatric Warmline at 1-866-637-2342, for free consultation Monday-Friday from 8:00am — 5:00pm (calls after 5:00pm or on holidays/weekends will be returned the next business day). The National Perinatal HIV Hotline also can be consulted and provides free clinical consultation 24 hours/day, at 1-888-448-8765.
At each visit, clinicians should:
- Educate and demonstrate to the caregiver how to measure and administer the correct ZDV dosage to be given to the infant because the dosage will change as the infant’s weight changes
- Recommend and provide infant oral syringes for administering accurate ZDV dosages
- Use vocabulary that caregivers can understand, regardless of educational level, and provide written information that is well organized and easy to understand
- Document in the medical record that administration of the accurate ZDV dosage was discussed with the caregiver
The interval during which infant prophylaxis can be initiated and still be of benefit is undefined; however, infant prophylaxis should be initiated as soon as possible after delivery. A study conducted in New York State demonstrated loss of efficacy when prophylaxis was delayed beyond 48 hours after birth.1,2
Dosage of infant ZDV is based on weight; therefore, dose adjustments are needed as the infant’s weight changes. At each visit, the clinician should ensure the mother is administering the ZDV dosage correctly. When a change in dosage is necessary based on infant’s weight change, the clinician should ensure that the caregiver understands how to measure and administer the new dosage. Comparisons of dosage delivery devices have demonstrated that accurate doses are more likely to be delivered when oral syringes are used.3
Anemia has been associated with the use of ZDV; therefore, some experts recommend obtaining a complete blood count (CBC) and differential prior to initiating ZDV. (BIII) If CBC and differential is obtained, initiation of ZDV prophylaxis should not be delayed while awaiting the results of the CBC. Hematologic abnormalities are most common in pre-term infants.4 Anemia generally resolves by 12 weeks; a baseline CBC is most useful for identifying a child at risk for developing severe anemia while receiving ZDV. Hematologic monitoring of the infant after birth is an individualized decision based on several factors, such as gestational age at birth, maternal antepartum regimen, and medications given to the infant. For infants who experience significant ZDV toxicity, consideration should be given to decreasing the duration of ZDV from 6 weeks to 4 weeks.5 The 4-week regimen has been shown to allow earlier recovery from anemia.5
Birth facilities should routinely stock liquid formulations of ZDV and NVP for immediate use in infants born to HIV-infected mothers, as indicated in Table 1.
Nevirapine is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pediatric drug formulation and neonatal dosing information6; currently, no protease inhibitors are recommended for neonatal use. Toxicities from nevirapine in the infant are rare but have included severe and potentially life-threatening rash and hepatic toxicity. Toxicities are much more common with nevirapine dosing for chronic infection than with the three-dose prophylactic regimen recommended for some neonates7-10; routine monitoring of serum liver enzyme levels is not indicated with short-term nevirapine dosing. For infants who receive nevirapine as prophylaxis but still become infected, resistance to nevirapine can occur.11
Duration of Antiretroviral Prophylaxis Regimen
In the United States, the current recommendation is 6 weeks of ZDV prophylaxis; however, this Committee has begun to review the evidence to support the use of a 4-week ZDV regimen in some infants who are at lower risk for MTCT.12 An update will be issued upon completion of the review.
A. Newborn Antiretroviral Prophylaxis: Specific Scenarios
1. Infants Born to Mothers Who Received Antepartum Antiretroviral Therapy with Undetectable HIV Viral Load Levels at Delivery
The risk of HIV acquisition is low in infants born to women who received standard ART regimens during pregnancy with undetectable viral loads at delivery. These infants should receive the 6-week regimen for ZDV infant prophylaxis.13,14 In this situation, adding additional ARV drugs to the ZDV regimen to reduce transmission risk is not recommended because the benefit would be very limited.
2. Infants Born to Mothers Who Received Only Intrapartum Prophylaxis
Infant prophylaxis is a critical component of prevention of HIV transmission when the mother did not receive any ARV drugs antepartum. In the PETRA study, intrapartum prophylaxis alone, without infant prophylaxis, was ineffective in reducing perinatal transmission.15 In the NICHD-HPTN 040/PACTG 1043 randomized clinical trial of ARV prophylactic regimens for infants born to mothers who had not received antepartum therapy, a majority of the mothers did not receive intrapartum prophylaxis; however, multi-drug infant prophylaxis alone was effective in preventing HIV transmission.7
3. Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs
The two-drug regimen of 6 weeks of ZDV plus three doses of nevirapine in the first week of life (see Table 1) is recommended for infants whose mothers did not receive antepartum or intrapartum ARV drugs based on the results of the randomized controlled clinical trial NICHD-HPTN 040/PACTG 1043. This trial demonstrated increased efficacy of either two- or three-drug regimens (2.2% to 2.4% transmission) in reducing intrapartum transmission compared with use of ZDV alone (4.9%) in infants born to mothers who did not receive antepartum or intrapartum ARV drugs.7
In NICHD-HPTN 040/PACTG 1043, the 2-drug regimen used was ZDV + nevirapine (Table 1); the three-drug regimen used was ZDV + lamivudine + nelfinavir.7 Nelfinavir is no longer available in a pediatric formulation in the United States, and other protease inhibitors have neonatal toxicities, poor pharmacokinetics, or both, which limits their use in infants. Thus, nevirapine is currently the only recommended ARV agent to add to the ZDV prophylactic regimen in the newborn period based on availability of a pediatric formulation and its low toxicity profile. Use of regimens other than those shown in Table 1 should be considered only in consultation with a pediatrician with experience in HIV treatment and management.
This Committee continues to recommend that regimens other than those shown in Table 1 should only be used in consultation with a pediatrician with experience in HIV treatment and management. Key issues that warrant caution include 1) the absence of safety data related to the high therapeutic dosing of nevirapine in infants under 2 weeks of age, and 2) the use of lopinavir-ritonavir in infants under 2 weeks of age, which is contraindicated due to toxicity.
4. Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs but Have Suboptimal Viral Suppression Near Delivery
Providers should consult with a pediatric provider who has experience with HIV treatment and management of HIV-exposed infants to determine whether to use the two-drug regimen of ZDV + NVP (see Table 1) for infants of mothers with suboptimal viral suppression. (BIII)
The risk of perinatal HIV transmission is higher in infants born to mothers with higher viral load levels near delivery, particularly with vaginal deliveries.17-19 In the Women and Infants Transmission Study (WITS), the risk of transmission of HIV was ≤1.8% in women who received three-drug ART during pregnancy and had HIV RNA levels < 30,000 copies/mL at delivery; risk increased to 4.8% in women with HIV RNA levels ≥30,000 copies/mL.19
No specific data address whether adding an additional agent to the prophylactic regimen provides additional protection against transmission when maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery is significant. A two-drug regimen of ZDV + NVP should be considered in consultation with a pediatric provider who has experience with HIV treatment and management (see Table 1).7 Initiation of ZDV should not be delayed while awaiting consultation.
5. Infants Born to Mothers with Antiretroviral Drug-Resistant Virus
Before delivery, clinicians should consult a pediatric provider who has experience with HIV treatment and management when treating infants born to mothers with known or suspected drug resistance. (BIII)
The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus is unknown, and few ARV agents are able to be safely administered to newborns and infants. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should be determined before delivery in consultation with an experienced provider in pediatric HIV infection.
B. Antiretroviral Drug Dosing for Premature Infants
Clinicians should consult a pediatric provider who has experience with HIV treatment and management to determine the optimal regimen when the neonate is at high risk for HIV infection. (BIII)
Clinicians should consult with a pediatric provider who has experience with HIV treatment and management before administering nevirapine to neonates who are <1.5 kg or <32 weeks’ estimated gestational age at birth.
Use of ARV agents other than ZDV and nevirapine is not recommended in premature infants because data on dosing and safety are lacking. However, in situations where there is high risk of infant HIV infection, consultation with a pediatric provider who has experience with ART is recommended to determine whether the benefits of an ARV prophylactic regimen other than ZDV + nevirapine outweigh the potential risks.
ZDV and nevirapine both have prolonged half-lives in premature infants.20-22 Dosing of ZDV for premature infants is outlined in Table 1. Few data are available to guide dosing of nevirapine in infants <1.5 kg or <32 weeks’ estimated gestational age at birth.
II. DIAGNOSTIC TESTING
New York State Department of Health (NYSDOH) recommends that all NYS birth facilities and pediatricians caring for HIV-exposed infants use the Pediatric HIV Testing Services at the Wadsworth Center.
In New York State, HIV qualitative RNA testing (nucleic acid test or NAT) is recommended for early detection of HIV infection in infants. Testing should be performed at the following ages: (AII)
- Within 48 hours of birth (BIII)
- At 2 weeks of age (AII)
- At 4 to 6 weeks of age (AII)
- At 4 to 6 months of age (AII)
Positive HIV NAT results at any age should be confirmed by repeat testing as soon as possible on a new sample. (AII) Two independent positive test results definitively diagnose pediatric HIV infection in HIV-exposed infants and subsequent testing is not necessary.
Once a positive HIV test result is confirmed, the clinician should:
- Consult a provider with experience in pediatric HIV care (AI)
- Discontinue perinatal prophylactic ZDV, if still being administered (AI)
- Evaluate for initiation of combination ART as soon as possible (AI)
Two negative HIV NAT results, one obtained ≥4 weeks of age and one obtained ≥4 months of age, definitively exclude pediatric HIV infection in HIV-exposed infants. (AII)
Early diagnosis of HIV infection in infants is important so that treatment with ART may be initiated as soon as possible. In NYS, HIV qualitative RNA diagnostic testing is recommended within 48 hours of birth, at age 2 weeks, at age 4 to 6 weeks, and at age 4 to 6 months. The NYSDOH has a free pediatric HIV diagnostic testing service, including overnight shipping, for NYS providers caring for HIV-exposed infants. The Pediatric HIV Testing Service uses the only FDA-approved qualitative RNA test (Aptima) for diagnosing HIV infection. Quantitative RNA tests (viral load) are not FDA approved for diagnostic purposes.
Providers who have not previously used the Testing Service should contact the Testing Service to obtain the specimen collection kits and shipping supplies. The provider should set up a tracking system to ensure that results for all HIV diagnostic testing are obtained promptly. For more information, including contacts, please visit the website for the Pediatric HIV Testing Service at Wadsworth Center.
Two negative HIV NAT results, one at >4 weeks of age and a second at >4 months of age, definitively excludes pediatric HIV infection. The infant may then be treated as a non-HIV-infected infant.
For more information, see Diagnosis of Pediatric HIV Infection in HIV-Exposed Infants.
III. PNEUMOCYSTIS JIROVECII PNEUMONIA (PCP) PROPHYLAXIS
Clinicians should initiate prophylaxis against PCP at 6 weeks of age for all HIV-exposed infants unless HIV diagnostic testing definitively or presumptively excludes HIV infection (see Table 3). Prophylaxis should be continued until the diagnosis of HIV infection is presumptively or definitively excluded (see definitions of exclusion below). (AII)
Early diagnosis and treatment of HIV-infected infants with ART has substantially decreased the risk of PCP in HIV-infected infants. Nevertheless, PCP continues to be the presenting HIV-associated infection in many HIV-infected infants.
PCP prophylaxis is recommended at 6 weeks of age for all HIV-exposed infants until diagnostic testing definitively or presumptively excludes HIV infection.
- Presumptive exclusion: Two negative HIV NAT results, one at ≥2 weeks of age and the other at >4 weeks of age
- Definitive exclusion: Two negative HIV NAT results, one at >4 weeks of age and a second at >4 months of age (see Section II. Diagnostic Testing)
PCP prophylaxis may be withheld when HIV infection is either definitively or presumptively excluded. If the infant is found to be HIV-infected, PCP prophylaxis should be continued, and the infant should be referred to a pediatric provider with experience in the care of HIV-infected children.
For more information about PCP prophylaxis, see Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children.
IV. FEEDING HIV-EXPOSED INFANTS
In New York State, breastfeeding by HIV-infected women is contraindicated, even when the mother is receiving combination ART. (AI)
Clinicians should strongly advise breastfeeding mothers with newly suspected or diagnosed HIV infection to discontinue breastfeeding immediately. Clinicians should consult with a pediatric provider who has experience with HIV treatment and management to determine whether prophylaxis should be given to the infant.
Clinicians should advise HIV-infected women to avoid premasticating food for infants. (AII)
HIV can be transmitted through breastfeeding. Infants whose mothers are HIV-infected, or whose HIV status is undetermined, should not be breastfed.23 The risk of HIV transmission depends on multiple infant and maternal factors, including maternal viral load and CD4 cell count.24 In the United States, where adequate formula preparations are readily available, HIV-exposed infants should not be breastfed.
When HIV infection has not been definitively excluded in the mother, pumping and discarding breast milk may be considered while awaiting results from confirmatory diagnostic testing. If HIV infection is definitively excluded, the mother may then initiate breastfeeding.
Studies have reported pediatric HIV transmission attributed to premasticating food for children.25,26 HIV-infected mothers and mothers whose HIV infection status is not known should be advised against premasticating food for infants.
Clinicians should follow the Centers for Disease Control and Prevention (CDC) recommended immunization schedules for HIV-exposed and HIV-infected infants.
During the first months of life, HIV-exposed infants should follow the same routine immunization schedule recommended for infants who were not exposed to HIV. For infants who test positive for HIV infection, modifications regarding live vaccines may be necessary.
VI. FREQUENCY OF VISITS AND LONG-TERM FOLLOW-UP
All HIV-exposed infants should receive care from, or in consultation with, a pediatrician experienced with HIV treatment and management by at least 2 weeks of age, and again at 1 month, 2 months, 4 months, and 6 months.
Clinicians should evaluate for potential mitochondrial dysfunction in ARV-exposed children who develop significant organ system abnormalities. (BIII)
- Document in utero exposure to ARV drugs in the patient’s permanent medical record (AIII)
- Report cases of prenatal exposure to ARV drugs to the Antiretroviral Pregnancy Registry
HIV-exposed infants should receive care from, or in consultation with, a pediatrician experienced with HIV treatment and management by at least 2 weeks of age, and again at 1 month, 2 months, 4 months, and 6 months. These visits will coincide with HIV diagnostic testing recommendations.
ARV drugs have not been determined to be carcinogenic or mutagenic in humans; however, that possibility cannot be excluded until long-term studies of in utero ART-exposed children are completed. Follow-up data from PACTG 076 showed no long-term changes in growth, development, or risk of malignancies in children through 5.6 years of age who received the ZDV regimen.27 In utero exposure to ARV drugs should be documented in the child’s permanent medical record, and follow-up should continue into adulthood.
The Antiretroviral Pregnancy Registry is a voluntary reporting system that collects data about infants exposed to ART medications in utero. The data are analyzed on a regular basis by an advisory committee of pediatricians and obstetricians to look for an increased incidence of congenital defects, malignancies, death, or other untoward effects in children exposed to ART medications. For more information, see the Antiretroviral Pregnancy Registry.28
1. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med 1998;339:1409-1414. [PubMed]
2. Fiscus SA, Schoenbach VJ, Wilfert C. Short courses of zidovudine and perinatal transmission of HIV. N Engl J Med 1999;340:1040-1043. [PubMed]
3. Sobhani P, Christopherson J, Ambrose PJ, et al. Accuracy of oral liquid measuring devices: Comparison of dosing cup and oral dosing syringe. Ann Pharmacother 2008;42:46-52. [PubMed]
4. Read JS, Huo Y, Patel K, et al. Laboratory abnormalities among HIV-exposed, uninfected infants: IMPAACT Protocol P1025. J Pediatr Infect Dis Soc 2012;1:92-102.
5. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants: Implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis 2010;29:376-379. [PubMed]
6. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nevirapine concentrations in newborns receiving an extended prophylactic regimen. J Acquir Immune Defic Syndr 2008;47:334-337. [PubMed]
7. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012;366:2368-2379. [PubMed]
8. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008;359:119-129. [PubMed]
9. Six Week Extended-Dose Nevirapine (SWEN) Study Team, Bedri A, Gudetta B, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: An analysis of three randomised controlled trials. Lancet 2008;372:300-313. [PubMed]
10. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): A randomised, double-blind, placebo-controlled trial. Lancet
11. Fogel J, Hoover DR, Sun J, et al. Analysis of nevirapine resistance in HIV-infected infants who received extended nevirapine or nevirapine/zidovudine prophylaxis. AIDS 2011;25:911-917. [PubMed]
12. Ferguson W, Goode M, Walsh A, et al. Evaluation of 4 weeks’ neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J 2011;30:408-412. [PubMed]
13. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;33:1173-1180.
14. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: A randomized trial. JAMA 2002;288:189-198. [PubMed]
15. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): A randomised, double-blind, placebo-controlled trial. Lancet 2002; 359:1178-1186. [PubMed]
16. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 2013;369:1828-1835. [PubMed]
17. Garcia PM, Kalish LA, Minkoff H, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med 1999;341:394-402. [PubMed]
18. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999;341:385-393. [PubMed]
19. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002;29:484-494. [PubMed]
20. Mirochnick M, Capparelli E, Connor J, et al. Pharmacokinetics of zidovudine in infants: A population analysis across studies. Clin Pharmacol Ther 1999;66:16-24. [PubMed]
21. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003;142:47-52. [PubMed]
22. Mugabo P, Els I, Smith J, et al. Nevirapine plasma concentrations in premature infants exposed to single-dose nevirapine for prevention of mother-to-child transmission of HIV-1. S Afr Med J 2011;101:655-658. [PubMed]
23. Committee on Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics 2013;131;391-396. [PubMed]
24. Kuhn L, Reitz C, Abrams EJ, et al. Breastfeeding and AIDS in the developing world. Curr Opin Pediatr 2009;21:83-93. [PubMed]
25. Ivy W 3rd, Dominguez KL, Rakhmanina NY, et al. Premastication as a route of pediatric HIV transmission: Case-control and cross-sectional investigations. J Acquir Immune Defic Syndr 2012;59:207-212. [PubMed]
26. Gaur AH, Dominguez KL, Kalish ML, et al. Practice of feeding premasticated food to infants: A potential risk factor for HIV transmission. Pediatrics 2009;124:658-666. [PubMed]
27. Culnane M, Fowler M, Lee SS, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA 1999;281:151-157. [PubMed]
28. Antiretroviral Pregnancy Registry. PharmaResearch Corporation. Wilmington, NC, 2012. Available at: http://www.apregistry.com