Perinatal Transmission Prevention Guideline Committee, January 2014
|JANUARY 2014 UPDATES|
The recommended routine postnatal prophylaxis for all HIV-exposed infants has changed.
The new recommended dosing is as follows: Zidovudine (ZDV) syrup, 4 mg/kg per dose PO given twice daily through 6 weeks of age, started as soon as possible (within 6 hours, and no later than 12 hours of delivery). See text for dosing for premature infants <35 weeks’ gestation.
Clinical scenarios that warrant supplemental prophylaxis are as follows:
The recommended supplemental postnatal prophylaxis is as follows:
When treating infants born to mothers with known or suspected drug resistance, clinicians should consult with a pediatric provider who has experience with HIV treatment and management. Whenever possible, consultation should occur before delivery.
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.
Newborn Antiretroviral Prophylaxis for HIV-Exposed Infants
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 .
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. 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 . 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 . The 4-week regimen has been shown to allow earlier recovery from anemia .
ARV Prophylaxis for HIV-Exposed Infants
Routine postnatal ARV prophylaxis for ALL HIV-exposed infants:
- Full-Term Newborn Regimen (≥35 weeks’ gestation): Start as soon as possible (within 6 hours, and no later than 12 hours of delivery): Zidovudine (ZDV) syrup, 4 mg/kg per dose PO give twice daily through 6 weeks of age [a]
- Preterm Newborn Regimen–Start as soon as possible (within 6 hours, and no later than 12 hours of delivery)
- For ≥30 to <35 weeks’ gestation: ZDV 2 mg/kg per dose PO [or 1.5 mg/kg per dose IV] given every 12 hours, then advance to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours beginning at age 15 days through 6 weeks of age
- For <30 weeks’ gestation: ZDV 2 mg/kg per dose PO (or 1.5 mg/kg per dose IV) given every 12 hours, then advance to 3 mg/kg/dose PO (2.3 mg/kg/dose IV) every 12 hours beginning at 4 weeks of age through 6 weeks of age
Supplemental postnatal ARV prophylaxis: 2-Drug Regimen: ZDV + NVP
See scenarios below describing which infants should receive supplemental prophylaxis. Consultation with a pediatric provider who has experience with HIV treatment and management is advised before administering nevirapine to neonates who are <1.5 kg or <32 weeks estimated gestational age at birth.
- ZDV: 4 mg/kg per dose PO twice per day; birth through 6 weeks plus
- Nevirapine (NVP):
- BW >2 kg: 12 mg PO per dose
- BW 1.5-2 kg: 8 mg PO per dose
- 3 doses in first week of life:
- dose 1: within first 48 hr of birth;
- dose 2: 48 hr after first dose;
- dose 3: 96 hr after second dose
- If oral ZDV cannot be tolerated: Administer ZDV 3.0 mg/kg per dose IV every 12 hours, started as soon as possible after birth (within 6 hours, and no later than 12 hours of delivery).
|Birth facilities should routinely stock liquid formulations of ZDV and NVP for immediate use in infants born to HIV-infected mothers, as indicated in the text.|
Nevirapine is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pediatric drug formulation and neonatal dosing information ; 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 neonates [7-10]; 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 .
Clinical scenarios for which supplemental ARV prophylaxis is indicated to prevent MTCT:
- Mother received no antepartum therapy and only intrapartum ZDV: 2-drug regimen: ZDV + NVP
- Mother received no antepartum and no intrapartum prophylaxis: 2-drug regimen: ZDV + NVP
- Mother received antepartum therapy with incomplete (HIV RNA >1,000 copies/mL) or unknown degree of viral suppression: Scheduled elective cesarean section; consider the 2-drug regimen of ZDV + NVP in consultation with a pediatric provider who has experience with HIV treatment and management
- Mother has known drug-resistant HIV: Consider a 2- or 3-drug regimen in consultation with a pediatric provider who has experience with HIV treatment and management
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 . An update will be issued upon completion of the review.
- Infants Born to Mothers Who Received Antepartum ART 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.
- 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 . 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 .
- Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum ARVs
The two-drug regimen of 6 weeks of ZDV plus three doses of nevirapine in the first week of life (see above) 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 .
In NICHD-HPTN 040/PACTG 1043, the 2-drug regimen used was ZDV + nevirapine (see above); the three-drug regimen used was ZDV + lamivudine + nelfinavir . 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 above should be considered only in consultation with a pediatrician with experience in HIV treatment and management.
In early 2013, a case of a “functional cure” of an HIV-infected infant was reported . The infant was born at 35 weeks’ gestation by vaginal delivery to a woman who received no prenatal care and was diagnosed with HIV infection by rapid testing during delivery. No intrapartum ARV prophylaxis could be given. At 30 hours of age, the infant was given ZDV, lamivudine, and nevirapine (NVP was given at higher therapeutic doses rather than standard prophylactic doses). Lopinavir-ritonavir was substituted for nevirapine at 7 days of age; this decision preceded warnings from the FDA against the use of lopinavir-ritonavir in infants younger than 14 days. Numerous DNA and RNA assays confirmed HIV infection in the infant. Therapy was discontinued by the mother at 18 months, but when the child returned for care at 2 years of age, levels of plasma viral RNA and HIV antibodies remained undetectable. Further investigation is ongoing, and clinical trials are planned to address whether early administration of therapeutic ART regimens is safe and effective in infants.
This Committee continues to recommend that regimens other than those shown in the text 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.
- Infants Born to Mothers Who Have Received Antepartum/Intrapartum ARVS But Have Suboptimal Viral Suppression Near Delivery
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 .
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 above) . Initiation of ZDV should not be delayed while awaiting consultation.
- Infants Born to Mothers with ARV Drug-Resistant Virus
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.
ARV Dosing for Premature Infants
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 above. Few data are available to guide dosing of nevirapine in infants <1.5 kg or <32 weeks’ estimated gestational age at birth.
- 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]
- Fiscus SA, Schoenbach VJ, Wilfert C. Short courses of zidovudine and perinatal transmission of HIV. N Engl J Med 1999;340:1040-1043. [PubMed]
- 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]
- Read JS, Huo Y, Patel K, et al. Laboratory abnormalities among HIV-exposed, uninfected infants: IMPAACT Protocol P1025. J Pediatr Infect Dis Soc2012;1:92-102.
- 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]
- 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]
- Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med2012;366:2368-2379. [PubMed]
- Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med2008;359:119-129. [PubMed]
- 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]
- 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
- 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]
- 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]
- 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.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Mirochnick M, Capparelli E, Connor J, et al. Pharmacokinetics of zidovudine in infants: A population analysis across studies. Clin Pharmacol Ther1999;66:16-24. [PubMed]
- Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003;142:47-52. [PubMed]
- 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]
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.
Pneumocystis jirovecii Pneumonia (PCP) Prophylaxis
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.
|DEFINITIONS OF EXCLUSION OF HIV INFECTION FOR HIV-EXPOSED INFANTS|
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.
Pneumocystis jirovecii Pneumonia (PCP) Prophylaxis for HIV-Exposed Infants*
Preferred regimen: Trimethoprim-sulfamethoxazole (TMP-SMX):
- TMP 5 mg/kg/day (or 150 mg/m2/day), with
- SMX 25 mg/kg/day (or 750 mg/m2/day) PO in 2 equally divided doses twice daily 3x/weekly on consecutive days
- Acceptable alternative schedules for TMP-SMX prophylaxis (using same dose as above):
- Single daily dose PO, 3x/weekly on consecutive days or
- Equally divided dose, given PO twice daily, 7 days/week or
- Equally divided dose, given PO twice daily, 3x/weekly on alternate days
- (Max daily dose: 320 mg TMP/1600 mg SMX)
Alternative regimens if TMP-SMX is not tolerated:
- Dapsone: 2 mg/kg PO once daily (Max daily dose: 100 mg) or 4 mg/kg PO once weekly (Max daily dose: 200 mg)
- Age 6 wks to ≤3 mos: 30 mg/kg PO once daily (Max daily dose: 1500 mg)
- Age 4 mos to 1 yr: 45 mg/kg PO once daily (Max daily dose: 1500 mg)
*Age 6 weeks to 1 year without presumptive or definitive exclusion of HIV infection.
Derived from American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
Feeding HIV-Exposed Infants
HIV can be transmitted through breastfeeding. Infants whose mothers are HIV-infected, or whose HIV status is undetermined, should not be breastfed .The risk of HIV transmission depends on multiple infant and maternal factors, including maternal viral load and CD4 cell count . 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 [3,4]. HIV-infected mothers and mothers whose HIV infection status is not known should be advised against premasticating food for infants.
- Committee on Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics 2013;131;391-396. [PubMed]
- Kuhn L, Reitz C, Abrams EJ, et al. Breastfeeding and AIDS in the developing world. Curr Opin Pediatr 2009;21:83-93. [PubMed]
- 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]
- 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]
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.
Frequency of Visits and Long-Term Follow-Up
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 ofin 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 . 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 .
- 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]
- Antiretroviral Pregnancy Registry. PharmaResearch Corporation. Wilmington, NC, 2012. Available at: http://www.apregistry.com
Perinatal Transmission Prevention Guideline Committee, January 2014
|ALL RECOMMENDATIONS: CARE OF THE HIV-EXPOSED INFANT WITH INDETERMINATE STATUS|
Newborn Antiretroviral Prophylaxis for HIV-Exposed Infants
Pneumocystis jirovecii Pneumonia (PCP) Prophylaxis
Feeding HIV-Exposed Infants
Frequency of Visits and Long-Term Follow-Up