Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Infant Antiretroviral Prophylaxis
(Last updated:3/28/2014; last reviewed:3/28/2014)
- The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is generally recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (AI). However, a 4-week neonatal chemoprophylaxis regimen can be considered when the mother has received standard combination antiretroviral therapy (cART) during pregnancy with consistent viral suppression and there are no concerns related to maternal adherence (BII).
- Zidovudine, at gestational age-appropriate doses, should be initiated as close to the time of birth as possible, preferably within 6 to 12 hours of delivery (AII).
- Infants born to HIV-infected women who have not received cART should receive prophylaxis with zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (i.e., at birth, 48 hours later, and 96 hours after the second dose), begun as soon after birth as possible (AI).
- In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by maternal counseling on the potential risks and benefits of this approach (BIII).
- For infants born to mothers with unknown HIV status, expedited (rapid) HIV testing of mothers and/or infants is recommended as soon as possible, either during labor or after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis if the initial expedited test is positive (AII). If supplemental testing is negative, ARV prophylaxis can be discontinued.
- In the United States, the use of ARV drugs other than zidovudine and nevirapine cannot be recommended in premature infants as prophylaxis to prevent transmission because of lack of dosing and safety data (BIII).
- The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, including infant care.
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
General Considerations for Choice of Infant Prophylaxis
All HIV-exposed infants should receive postpartum antiretroviral (ARV) drugs to reduce perinatal transmission of HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is generally recommended for all HIV-exposed infants.1,2
However, a 4-week neonatal chemoprophylaxis regimen can be considered when the mother has received standard combination antiretroviral therapy (cART) during pregnancy with consistent viral suppression and there are no concerns related to maternal adherence (see Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with Effective Viral Suppression below ).3,4
Table 8 shows recommended zidovudine dosing based on gestational age, birth weight and the status of maternal antepartum ARV regimens.
The risk of transmission is increased when maternal viral load at delivery is high or maternal antepartum and/or intrapartum prophylaxis was incomplete or not received. In these situations, the potential benefit of combining zidovudine infant prophylaxis with additional ARV drugs must be weighed against the potential risks to infants of multiple drug exposure. In the following sections, we present available data and recommendations for management of infants born to mothers:
- Who received antepartum/intrapartum ARV drugs with effective viral suppression;
- Who received antepartum and intrapartum ARV drugs but who had suboptimal viral suppression at delivery, particularly if delivery was vaginal;
- Who received only intrapartum ARV drugs;
- Who received neither antepartum nor intrapartum ARV drugs;
- With unknown HIV status; and
- With known ARV drug-resistant virus.
In each of these situations, there is a spectrum of transmission risk that depends on a number of maternal and infant factors, including maternal viral load, mode of delivery, and gestational age at delivery. The risks and benefits of infant exposure to ARV drugs in addition to zidovudine will differ depending on where the mother/child falls in the risk spectrum. Thus, a generic recommendation cannot be made regarding use of combination drug regimens for infant prophylaxis. Each situation needs to be considered individually, balancing potential benefits (in terms of preventing perinatal transmission of HIV) with risks (in terms of toxicity to the infant). In addition, appropriate drug formulations and dosing regimens for neonates are incompletely defined and data are minimal on the safety of combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis and the Pediatric Antiretroviral Guidelines
Data from the NICHD-HPTN 040/PACTG 1043 study have provided guidance for management of infants born to women who received no ARV prophylaxis during pregnancy. In this study, 1,746 formula-fed infants born to HIV-infected women who did not receive any ARV drugs during pregnancy were randomized to one of three infant prophylaxis regimens: the standard 6-week zidovudine regimen; 6 weeks of zidovudine plus three doses of nevirapine given during the first week of life (first dose at birth–48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose); and 6 weeks of zidovudine plus 2 weeks of lamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower in the two- and three-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for 6 weeks of zidovudine alone; P
= .046 for each experimental arm vs. zidovudine alone).5
Although transmission rates with the two combination regimens were similar, neutropenia was significantly more common with the three-drug regimen than with the two-drug or zidovudine-alone regimen (27.5% vs. 15%, P
<.0001). In other studies, significantly higher rates of neutropenia and anemia have been reported with co-administration of zidovudine and lamivudine to infants.6
Thus, based on comparable efficacy and reduced toxicity, the Panel recommends 6 weeks of zidovudine plus three doses of nevirapine for infants whose mothers have not received antepartum ARVs (Table 8).
Despite the paucity of available data, the use of combination ARV prophylaxis for infants in high-risk situations is increasing. Surveillance of obstetric and pediatric HIV infection in the United Kingdom and Ireland through the National Study of HIV in Pregnancy and Childhood noted that between 2001 and 2004, 9% of HIV-exposed infants received triple-drug prophylaxis compared with 13% between 2005 and 2008.7
Similarly, in an Internet-based poll of 134 U.S.-based perinatal HIV service providers, 62% reported using combination postnatal prophylaxis in high-risk situations in the past year. Zidovudine, lamivudine, and nevirapine was the combination regimen used most often.8
The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) has pooled data from 5,285 mother-infant pairs included in eight European cohorts and evaluated the use of combination prophylaxis. Among the 1,105 infants receiving combination prophylaxis, 13.5% received zidovudine plus lamivudine, 22.7% received zidovudine plus single-dose nevirapine, 55.8% received zidovudine plus single-dose nevirapine plus lamivudine, and 4.4% received a regimen including a protease inhibitor (PI). In these observational cohorts, there was no difference in infant infection rates between one drug and combination prophylactic regimens.9
The authors concluded that the lack of difference may be related to residual confounding or the fact that combination prophylaxis may only be effective in a subset of infants.
A case of a “functional cure” of HIV in an infant was recently reported.10
The infant was born by vaginal delivery at 35 weeks’ gestation to a woman who received no prenatal care and was diagnosed as HIV-infected by rapid testing during labor; delivery occurred before maternal intrapartum ARV prophylaxis could be given. At age 30 hours, the infant initiated a regimen of zidovudine, lamivudine, and nevirapine (the latter drug administered at a higher therapeutic dose rather than standard prophylactic dosing). The infant was found to have a positive HIV DNA polymerase chain reaction (PCR) in a sample obtained at age 30 hours and an HIV RNA level of 19,812 copies/mL on an HIV RNA PCR assay performed at age 31 hours. Based on these tests, the infant was continued on treatment for HIV infection, thought to be acquired in utero
. Nevirapine was replaced by ritonavir-boosted lopinavir at day 7 of life (Note: This decision preceded warnings from the Food and Drug Administration (FDA) against use of ritonavir-boosted lopinavir in infants younger than age 14 days). At age 18 months, therapy was discontinued by the mother; levels of plasma RNA, proviral DNA, and HIV antibodies have remained undetectable in the child through age 30 months on no therapy. Further investigation is ongoing, and clinical trials are planned to address whether administration of a therapeutic combination ARV regimen to HIV-exposed high-risk infants could alter the establishment and long-term persistence of HIV infection and assess the safety of such an approach for the infant.
There are two key safety issues related to the choice of ARV drugs in this infant. First, although the use of nevirapine to prevent perinatal transmission has been found to be safe in neonates and low-birth-weight infants (see Antiretroviral Drug Dosing for Premature Infants), these prophylaxis-dose regimens target trough drug levels of 100 ng/mL, with peak levels averaging 1,000 to 1,500 ng/mL. However, there have been no studies in neonates under age 2 weeks or preterm infants to determine the appropriate dosing or safety of nevirapine administered at therapeutic doses, designed to maintain trough drug concentrations above 3,000 ng/mL and peak levels below 10,000 ng/mL for treatment of HIV-infected individuals. Second, ritonavir-boosted lopinavir is not recommended for neonates younger than age 14 days because of the potential for significant toxicity (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis). Therefore, the risks of this approach in terms of infant toxicity (particularly in preterm infants), as well as whether the functional cure can be replicated in additional infants, require further study before a general recommendation can be made.
In this and all other scenarios, decisions about use of combination ARV prophylaxis in infants should be made in consultation with a pediatric HIV specialist before delivery, if possible, and should be accompanied by a discussion with the mothers about potential risks and benefits of this approach.
The National Perinatal HIV Hotline
The National Perinatal HIV Hotline (888-448-8765) is a federally funded service providing free clinical consultation for difficult cases to providers caring for HIV-infected pregnant women and their infants, and can provide referral to local or regional pediatric HIV specialists.
Recommendations for Infant Antiretroviral Prophylaxis in Specific Clinical Situations
Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with Effective Viral Suppression
The risk of HIV acquisition is small in infants born to women who received standard ARV prophylaxis regimens during pregnancy and labor and had undetectable viral loads at delivery or by scheduled cesarean section to mothers with low viral loads at delivery. The optimal minimum duration of neonatal zidovudine chemoprophylaxis has not been established in clinical trials. In the United States, the standard 6-week infant zidovudine regimen has been recommended, based on data from PACTG studies 076 and 316 (both performed during an era when a greater proportion of women did not receive antenatal cART). In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regimen is now recommended for infants born to mothers who have received cART regimens and have viral suppression, with no apparent increase in the overall HIV perinatal transmission rate.3,4
Additionally, a 4-week zidovudine regimen has been reported to allow earlier recovery from anemia in otherwise healthy infants compared with the 6-week zidovudine regimen.11
Therefore, a 4-week zidovudine neonatal chemoprophylaxis regimen can be considered when a mother has received standard cART during pregnancy with consistent viral suppression and there are no concerns related to maternal adherence.
In infants born to women with effective viral suppression, combining zidovudine with additional ARV drugs to reduce transmission risk is not recommended because the risk of transmission is low and any potential benefit would be very limited. Any potential benefits must be balanced by the known toxicities of ARV drugs in infants.
Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs But Have Suboptimal Viral Suppression Near Delivery
All infants born to women who have received antepartum/intrapartum ARVs but with suboptimal viral suppression near delivery should receive zidovudine for 6 weeks. No specific data address whether a more intensive combination infant prophylaxis regimen (two or three drugs) provides additional protection against transmission when maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery is significant. Extrapolation of findings from the previously discussed NICHD-HPTN 040/PACTG 1043 study5
suggests that combination infant prophylaxis should be considered, depending on assessment of risk based on maternal viral load and mode of delivery. That decision should be made in consultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on the potential risks and benefits of this approach.
Many data support the observation that the risk of perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs as well as women receiving ARVs.12-14
Scheduled cesarean delivery is recommended for prevention of perinatal transmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA >1,000 copies/mL) near the time of delivery (see Intrapartum Care
and Transmission and Mode of Delivery
). In PACTG 316, transmission occurred in 0% of 17 infants when maternal HIV RNA levels at delivery were >10,000 copies/mL and delivery was by scheduled cesarean delivery.2
However, not all women with detectable viremia near delivery will undergo cesarean delivery. The risk of acquisition of HIV will be higher in infants born to mothers with higher viral loads near delivery, particularly if delivery is vaginal. The gradient of transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study (WITS), the risk of transmission of HIV was ≤1.8% in women who received cART and had HIV RNA levels <30,000 copies/mL at delivery; it increased to 4.8% in women with HIV RNA levels ≥30,000 copies/mL.14
Infants Born to Mothers Who Received Only Intrapartum Antiretroviral Drugs
All infants whose mothers have received only intrapartum ARV drugs should receive the two-drug regimen of 6 weeks of zidovudine plus three doses of nevirapine in the first week of life (first dose at birth to 48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose), based on the results of the NICHD-HPTN 040/PACTG 1043 study. Infant prophylaxis should be initiated as soon after delivery as possible. Infant prophylaxis is a critical component of prevention when no maternal antepartum ARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, without infant prophylaxis, is ineffective in reducing perinatal transmission.15
A study in Thailand indicated that longer infant prophylaxis with zidovudine (6 weeks versus 3 days) is required for optimal efficacy when maternal antenatal exposure to zidovudine is <4 weeks.16
In the NICHD-HPTN 040/PACTG 043 trial, 41% of women received zidovudine during labor. Administration of intrapartum zidovudine did not affect transmission rates.5
Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs
The two-drug regimen of 6 weeks of zidovudine plus three doses of nevirapine in the first week of life (first dose at birth to 48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose) is recommended for infants born to mothers who did not receive antepartum or intrapartum ARVs based on the results of the NICHD-HPTN 040/PACTG 1043 study, which demonstrated increased efficacy of combination regimens in reducing intrapartum transmission compared with use of zidovudine alone in infants.5
Prophylaxis should be initiated as soon after delivery as possible.
The interval during which infant prophylaxis can be initiated and still be of benefit is undefined. In the New York State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could be demonstrated.17
Data from animal studies indicate that the longer the delay in institution of prophylaxis, the less likely that infection will be prevented. In most studies of animals, ARV prophylaxis initiated 24 to 36 hours after exposure usually has been ineffective in preventing infection, although a delay in administration has been associated with decreased viremia.18-20
In the NICHD-HPTN 040/PACTG 1043 study, infant regimens were initiated within 48 hours of life and usually within 12 hours of life.5
Initiation of infant prophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days, infection already would be established in most infants.21
Initiating prophylaxis as soon after delivery as possible increases its potential efficacy and minimizes potential harm, such as development of resistant virus, if infection has occurred.
Infants Born to Mothers with Unknown HIV Infection Status
Expedited (previously referred to as “rapid”) HIV testing of mothers is recommended during labor for women with unknown HIV status and for mothers and/or infants as soon as possible after birth if expedited HIV testing was not performed during labor. Expedited test results should be available within 60 minutes. Commercially available antigen/antibody tests are preferred to those that test only for antibody. Oral fluid-based tests are not recommended for infant testing; blood or serum testing has notably better sensitivity in infants than does oral fluid testing.22
If expedited testing is positive, infant ARV prophylaxis should be initiated immediately, without waiting for the results of supplemental tests (see scenario: Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs). Expedited HIV testing should be available on a 24-hour basis at all facilities with a maternity service and/or neonatal intensive care, special care or newborn nursery. A positive initial test result in mothers or infants should be presumed to indicate maternal HIV infection until standard supplemental testing clarifies maternal status. A positive HIV antibody test in an infant indicates maternal but not necessarily infant HIV infection; diagnosis of HIV infection in infants younger than age 18 months requires virologic testing using a viral nucleic amplification test (NAT; includes DNA and RNA PCR and related assays). Initial positive HIV antibody tests can be confirmed using a recommended HIV-1/2 diagnostic testing algorithm.23
Supplemental tests should be performed on mothers (or their infants) as soon as possible after the initial positive test. If the supplemental test results on a mother (or infant) are negative, ARV prophylaxis can be discontinued. If the supplemental test results are positive, an HIV NAT should be obtained urgently from the newborn to determine the infant’s HIV infection status. If the HIV NAT is positive, ARV prophylaxis should be promptly discontinued and the infant should receive treatment for HIV infection with standard cART according to the Pediatric Antiretroviral Guidelines
Breastfeeding should be stopped until HIV infection is confirmed or ruled out in a woman who is suspected of being HIV-infected based on an initial positive antibody test result. Pumping and temporarily discarding or freezing breast milk can be recommended. If HIV infection is ruled out, breastfeeding can resume. If HIV infection is confirmed, breastfeeding should be discontinued permanently.
Infants Born to Mothers with Antiretroviral Drug-Resistant Virus
The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus is unknown. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery.
Data from WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viral populations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted.24,25
Thus, the 6-week infant zidovudine prophylaxis (along with maternal intravenous [IV] intrapartum zidovudine prophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations is identified.
Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (reduced viral fitness) and transmissibility.25
However, perinatal transmission of multidrug-resistant virus has been reported both in the United States and international settings.26-30
For these newborns, use of zidovudine in combination with other ARV drugs, selected on the basis of maternal virus resistance testing, should be considered. The efficacy of this approach for prevention of transmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosing regimens for neonates have not been established. Decisions regarding use of additional drugs should be made in consultation with a pediatric HIV specialist and will depend on maternal history of past and current ARV drug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, and availability of drug formulation and dosing information in the infant.
Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis
Infant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily of transient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see Initial Postnatal Management
). Data are limited on the toxicity to infants of exposure to multiple ARV drugs.
The latest information on neonatal dosing for ARV drugs can be found in the Pediatric Antiretroviral Guidelines
. Other than zidovudine, lamivudine is the nucleoside reverse transcriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies, neonatal exposure to combination zidovudine/lamivudine was generally limited to 115,31,32
or 2 weeks.5
Six weeks of infant zidovudine/lamivudine exposure also has been reported; these studies suggest that hematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had in utero
exposure to maternal combination therapy.
In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks of zidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a historical cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neutropenia in 18% of infants exposed to zidovudine/lamivudine, with 2% of infants requiring blood transfusion and 4% requiring treatment discontinuation for toxicity.6
Similarly, in a Brazilian study of maternal antepartum and 6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxicity was common, with anemia seen in 69% and neutropenia in 13% of infants.33
Tenofovir with and without emtricitabine has been investigated in several small studies to define the safety and pharmacokinetics (PKs) of the agents in newborns.34,35,36
However, at this time, tenofovir and emtricitabine are not generally recommended for use in infant prophylaxis by the Panel because data on appropriate dosing are limited and the safety of these agents in the neonate is not well defined.
Experience with other NRTI drugs for neonatal prophylaxis is more limited.37,38
Hematologic and mitochondrial toxicity may be more common with exposure to multiple versus single NRTI drugs.6,39-42
Nevirapine is the only non-nucleoside reverse transcriptase inhibitor drug with a pediatric drug formulation and neonatal prophylactic (but not therapeutic) dosing information (see the Adult and Adolescent Antiretroviral Guidelines
In rare cases, chronic multiple-dose therapeutic nevirapine therapy has been associated with severe and potentially life-threatening rash and hepatic toxicity. These toxicities have not been observed in infants receiving prophylactic dosing with single-dose nevirapine, the 2-drug zidovudine regimen plus 3 doses of nevirapine in the first week of life in NICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophylaxis daily for 6 weeks to 6 months to prevent transmission of HIV via breast milk.5,44-47
Resistance to nevirapine can occur, however, with exposure to nevirapine in infants who become infected despite prophylaxis.48,49
ARV drug-resistance testing is recommended for all HIV-infected infants before initiation of cART (see the Adult and Adolescent Antiretroviral Guidelines
Of the PIs, pediatric drug formulations are available for ritonavir-boosted lopinavir, ritonavir, darunavir, tipranavir, and fosamprenavir, but their use in neonates in the first weeks of life is not recommended due to lack of dosing and safety information. No PK data are available for any PIs in the first 2 weeks of life. PK data are available for treatment of HIV-infected infants aged 2 to 6 weeks with ritonavir-boosted lopinavir. Although the lopinavir area under the curve (AUC) was significantly lower with dosing 300 mg lopinavir/75 mg ritonavir/m2
body surface area twice daily than observed for infants >6 weeks of age, treatment was well tolerated and 80% of 10 infants had viral control at 6 months.50
Studies are ongoing but data are not yet available for infants aged <2 weeks. However, in 4 premature infants (2 sets of twins) started on ritonavir-boosted lopinavir from birth, heart block developed that resolved after drug discontinuation.51,52
In studies of adults, both ritonavir and ritonavir-boosted lopinavir cause dose-dependent prolongation of the PR interval, and cases of significant heart block, including complete heart block, have been reported. Elevation of 17-hydroxyprogesterone and dehydroepiandrosterone-sulfate has also been associated with administration of ritonavir-boosted lopinavir compared with zidovudine in the neonatal period. Levels of 17-hydroxyprogesterone were greater in infants who were also exposed to ritonavir-boosted lopinavir in utero
compared with those exposed only in the neonatal period. Term infants were asymptomatic but three premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in one case, cardiogenic shock.53
Based on these and other post-marketing reports of cardiac toxicity (including complete atrioventricular block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, adrenal dysfunction, central nervous system depression, respiratory complications leading to death, and metabolic toxicity,54
predominantly in preterm neonates, the Food and Drug Administration now recommends that ritonavir-boosted lopinavir not
be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days.
Raltegravir is the only integrase inhibitor with an available pediatric drug formulation. However, it is not FDA-approved for use in infants aged <2 years and there are no PK and safety data on its use during the first weeks of life. Raltegravir competes with bilirubin for albumin binding sites, which could increase unconjugated bilirubin levels in the neonate. An in vitro
study has demonstrated that the effect of raltegravir on neonatal bilirubin binding is unlikely to be clinically significant unless raltegravir concentrations 50- to 100-fold higher than typical peak concentrations with usual dosing are reached.55
Use of raltegravir in neonates is not recommended until adequate PK and safety data are available.
Neonatal Antiretroviral Drug Dosing
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Table 8. Recommended Neonatal Dosing for Prevention of Perinatal Transmission of HIV
All HIV-Exposed Infants (initiated as soon after delivery as possible)
||≥35 weeks’ gestation at birth: 4 mg/kg/dose PO twice daily, started as soon after birth as possible and preferably within 6–12 hours of delivery (or, if unable to tolerate oral agents, 3 mg/kg/dose IV, beginning within 6–12 hours of delivery, then every 12 hours)
||Birth through 4-6 weeksa
||≥30 to <35 weeks’ gestation at birth: 2 mg/kg/dose PO (or 1.5 mg/kg/dose IV), started as soon after birth as possible, preferably within 6–12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days
||Birth through 6 weeks
||<30 weeks’ gestation at birth: 2 mg/kg body weight/dose PO (or 1.5 mg/kg/dose IV) started as soon after birth as possible, preferably within 6–12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours after age 4 weeks
||Birth through 6 weeks
|Additional Antiretroviral Prophylaxis Agents for HIV-Exposed Infants of Women who Received No Antepartum Antiretroviral Prophylaxis (initiated as soon after delivery as possible)
|In addition to ZDV as shown above, administer
|Birth weight 1.5–2 kg: 8 mg/dose PO
Birth weight >2 kg: 12 mg/dose PO
|3 doses in the first week of life
- 1st dose within 48 hrs of birth (birth–48 hrs)
- 2nd dose 48 hrs after 1st
- 3rd dose 96 hrs after 2nd
The recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally (PO) twice daily, beginning as soon after birth as possible and preferably within 6 to 12 hours of delivery15,44,56-63 (see Table 8). If an infant is unable to tolerate oral medications, the zidovudine prophylaxis regimen can be administered intravenously (IV). The zidovudine dosing requirements differ for premature infants and term infants (see Table 8 and Antiretroviral Drug Dosing for Premature Infants).
PKs and safety of the single-dose nevirapine regimen to mother and infant64 and chronic prophylactic nevirapine administration to infants to prevent HIV transmission during breastfeeding have been studied.65 The 3-dose extended nevirapine regimen that was used in NICHD-HPTN 040/PACTG 1043 and is recommended for HIV-exposed infants whose mothers did not receive ARV during the antepartum period has also been studied.43 Nevirapine concentrations were measured in 14 newborns participating in a PK substudy during the second week of life and in single samples from 30 more newborns on Days 10 to 14. The median nevirapine elimination half-life was 30.2 hours (range: 17.8–50.3 hours) and the concentration remained greater than the target of 100 ng/mL in all infants through Day 10 of life.
Antiretroviral Drug Dosing for Premature Infants
Dosing recommendations for premature infants are available for only zidovudine (prophylaxis and therapy) and nevirapine (prophylaxis only) (see Table 8). Zidovudine is primarily cleared through hepatic glucuronidation to an inactive metabolite; this metabolic pathway is immature in neonates, leading to prolonged zidovudine half-life and decreased clearance compared with older infants. Clearance is further decreased in premature infants because their hepatic metabolic function is less mature than in term infants.66,67
The recommended zidovudine dosage for preterm infants is shown in Table 8.
Nevirapine PKs have been described in low-birth-weight neonates receiving a single postnatal prophylaxis dose of the drug. In a study of 81 infants <37 weeks’ gestation, of which 29.6% were small for gestational age, half-lives were very long—median 59 hours in infants whose mothers received single-dose nevirapine and 69 hours in infants whose mothers did not receive single-dose nevirapine. AUC of nevirapine was higher and clearance lower (P
< .0001) in small-for-gestational-age infants.68
Use of ARV drugs other than zidovudine and nevirapine cannot be recommended at this time in premature infants because data on dosing and safety are lacking. Immature renal and hepatic metabolism can increase the risk of overdosing and toxicity. However, in situations where there is a high risk of infant HIV infection, consultation with a pediatric HIV specialist is recommended to determine if the benefits of combination ARV prophylaxis with drugs in addition to or other than zidovudine and nevirapine outweigh the potential risks.
Breastfeeding Infants of Mothers Diagnosed with HIV Infection Postpartum
Breastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeeding and suspected to have become HIV infected. Pumping and temporarily discarding or freezing breast milk can be recommended to mothers who are suspected of being HIV infected but whose infection is not yet confirmed and who want to continue to breastfeed. If HIV infection is ruled out, breastfeeding can resume. Breastfeeding is not recommended for women with documented HIV infection in the United States, including those receiving cART (see Infant Feeding Practices and Risk of HIV Transmission
The risk of acquisition of HIV associated with breastfeeding depends on multiple infant and maternal factors, including maternal viral load and CD4 T lymphocyte (CD4) cell count.70
Infants of women who develop acute HIV infection while breastfeeding are at greater risk of becoming infected than are those of women with chronic HIV infection71
because acute HIV infection is accompanied by a rapid increase in viral load and a corresponding decrease in CD4 cell count.72
Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothers who breastfed their infants prior to HIV diagnosis have yet to be defined. Some experts would consider the use of post-exposure prophylaxis in infants for 4 to 6 weeks after cessation of breastfeeding. Post-exposure prophylaxis, however, is less likely to be effective in this circumstance compared with other non-occupational exposures because the exposure to breast milk is likely to have occurred over a prolonged period rather than in a single exposure.73
Several studies of infants breastfed by women with chronic HIV infection have shown that daily infant nevirapine or nevirapine plus zidovudine can reduce the risk of postnatal infection during breastfeeding.44-46
The NICHD-HPTN 040/PACTG 1043 study demonstrated that combination ARV prophylaxis was more effective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who have not received antepartum ARV drugs.5
However, whether the combination regimens in this trial are effective for preventing transmission after cessation of breastfeeding in mothers with acute HIV infection is unknown.
Because of the high risk of postnatal transmission from a breastfeeding woman with acute HIV infection, an alternative approach favored by some experts would be to offer a combination ARV regimen that would be effective for treatment of HIV, should an infant become infected. If this route is chosen, current recommendations for treatment should guide selection of an appropriate combination ARV regimen (see the Pediatric Antiretroviral Guidelines
). Regardless of whether post-exposure prophylaxis or “pre-emptive therapy” is chosen, the optimal duration of the intervention is unknown. A 28-day course may be reasonable based on current recommendations for non-occupational HIV exposure.73
As in other situations, decisions regarding administration of a prophylactic or preemptive treatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternal counseling on the potential risks and benefits of this approach.
Infants should be tested for HIV infection at baseline and 4 to 6 weeks, 3 months, and 6 months after recognition of maternal infection to determine HIV status. In infants younger than age 18 months, HIV NAT should be used for diagnosis. HIV DNA PCR testing may be preferable for infants who are receiving combination ARV prophylaxis or preemptive treatment, because HIV RNA assays may be less sensitive in the presence of combination ARVs, which might lower infant plasma viral RNA to undetectable levels. However, HIV DNA PCR assays available in the United States may not detect non-subtype B or group O HIV as well as many HIV RNA assays. Therefore, if non-subtype B or group O HIV infection in an infant is considered possible, both HIV DNA and RNA assays should be obtained from the infant. HIV antibody assays can be used in infants older than age 18 months.
If an infant is already receiving post-exposure ARV prophylaxis and is found to be HIV-infected, prophylaxis should be discontinued and treatment for HIV infection initiated with standard cART according to the Pediatric Antiretroviral Guidelines
. Resistance testing should be performed and the cART regimen modified if needed (see the Pediatric Antiretroviral Guidelines
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