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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: March 28, 2014; last reviewed: March 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).43 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.
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 NVP
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
a A 6-week course of neonatal zidovudine is generally recommended. A 4-week neonatal zidovudine chemoprophylaxis regimen may be considered when the mother has received standard ART during pregnancy with consistent viral suppression and there are no concerns related to maternal adherence.
Key to Abbreviations: IV = intravenously; NVP = nevirapine; PO = orally; ZDV = zidovudine
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).69
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).
Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.
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(2):189-198. Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.
de Ruiter A, Mercey D, Anderson J, et al. British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008. HIV Med. 2008;9(7):452-502. Available at http://www.ncbi.nlm.nih.gov/pubmed/18840151.
Ferguson W, Goode M, Walsh A, Gavin P, Butler K. 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(5):408-412. Available at http://www.ncbi.nlm.nih.gov/pubmed/21266939.
Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.
Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA. 2001;285(16):2083-2093. Available at http://www.ncbi.nlm.nih.gov/pubmed/11311097.
Haile-Selassie H, Townsend C, Tookey P. Use of neonatal post-exposure prophylaxis for prevention of mother-to-child HIV transmission in the UK and Ireland, 2001-2008. HIV Med. 2011;12(7):422-427. Available at http://www.ncbi.nlm.nih.gov/pubmed/21251184.
McKeegan K, Rutstein R, Lowenthal E. Postnatal infant HIV prophylaxis: a survey of U.S. practice. AIDS Patient Care STDS. 2011;25(1):1-4. Available at http://www.ncbi.nlm.nih.gov/pubmed/21162689.
Chiappini E, Galli L, Giaquinto C, et al. Use of combination neonatal prophylaxis for the prevention of mother-to-child transmission of HIV infection in European high-risk infants. AIDS. 2013;27(6):991-1000. Available at http://www.ncbi.nlm.nih.gov/pubmed/23211776.
Persaud D, Gay H, al e. Absence of detectable HIV-1 viremia following treatment cessation in an infant. N Engl J Med. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/24152233.
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 J. 2010;29(4):376-379. Available at http://www.ncbi.nlm.nih.gov/pubmed/19949355.
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(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.
Garcia PM, Kalish LA, Pitt J, 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(6):394-402. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.
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(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.
Petra Study T. 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(9313):1178-1186. Available at http://www.ncbi.nlm.nih.gov/pubmed/11955535.
Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med. 2000;343(14):982-991. Available at http://www.ncbi.nlm.nih.gov/pubmed/11018164.
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(20):1409-1414. Available at http://www.ncbi.nlm.nih.gov/pubmed/9811915.
Van Rompay KK, Otsyula MG, Marthas ML, Miller CJ, McChesney MB, Pedersen NC. Immediate zidovudine treatment protects simian immunodeficiency virus-infected newborn macaques against rapid onset of AIDS. Antimicrob Agents Chemother. 1995;39(1):125-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/7695293.
Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science. 1995;270(5239):1197-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/7502044.
Bottiger D, Johansson NG, Samuelsson B, et al. Prevention of simian immunodeficiency virus, SIVsm, or HIV-2 infection in cynomolgus monkeys by pre- and postexposure administration of BEA-005. AIDS. 1997;11(2):157-162. Available at http://www.ncbi.nlm.nih.gov/pubmed/9030361.
Dunn DT, Brandt CD, Krivine A, et al. The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. AIDS. 1995;9(9):F7-11. Available at http://www.ncbi.nlm.nih.gov/pubmed/8527070.
American Academy of Pediatrics (AAP). Addendum evaluation and management of the infant exposed to HIV-1 in the United States. Pediatrics. 2012;130(6):64-65. Available at http://pediatrics.aappublications.org/content/130/6/64.full.pdf+html.
Centers for Disease Control and Prevention (CDC). DRAFT recommendations: Diagnostic laboratory testing for HIV infection in the United States. 2012. Available at http://www.cdc.gov/hiv/pdf/policies_Draft_HIV_Testing_Alg_Rec_508.2.pdf.
Colgrove RC, Pitt J, Chung PH, Welles SL, Japour AJ. Selective vertical transmission of HIV-1 antiretroviral resistance mutations. AIDS. 1998;12(17):2281-2288. Available at http://www.ncbi.nlm.nih.gov/pubmed/9863870.
Bauer GR, Colgrove RC, Larussa PS, Pitt J, Welles SL. Antiretroviral resistance in viral isolates from HIV-1-transmitting mothers and their infants. AIDS. 2006;20(13):1707-1712. Available at http://www.ncbi.nlm.nih.gov/pubmed/16931934.
Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1 despite viral suppression on an enfuvirtide-based treatment regimen. AIDS. 2005;19(9):989-990. Available at http://www.ncbi.nlm.nih.gov/pubmed/15905684.
Desai N, Mathur M. Selective transmission of multidrug resistant HIV to a newborn related to poor maternal adherence. Sex Transm Infect. 2003;79(5):419-421. Available at http://www.ncbi.nlm.nih.gov/pubmed/14573842.
De Jose MI, Ramos JT, Alvarez S, Jimenez JL, Munoz-Fernandez MA. Vertical transmission of HIV-1 variants resistant to reverse transcriptase and protease inhibitors. Arch Intern Med. 2001;161(22):2738-2739. Available at http://www.ncbi.nlm.nih.gov/pubmed/11732941.
Zeh C, Weidle PJ, Nafisa L, et al. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med. 2011;8(3):e1000430. Available at http://www.ncbi.nlm.nih.gov/pubmed/21468304.
Fogel J, Li Q, Taha TE, et al. Initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants. Clin Infect Dis. 2011;52(8):1069-1076. Available at http://www.ncbi.nlm.nih.gov/pubmed/21460326.
Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis. 1998;178(5):1327-1333. Available at http://www.ncbi.nlm.nih.gov/pubmed/9780252.
Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis. 2003;187(5):725-735. Available at http://www.ncbi.nlm.nih.gov/pubmed/12599045.
Lambert JS, Nogueira SA, Abreu T, et al. A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. Sex Transm Infect. 2003;79(6):448-452. Available at http://www.ncbi.nlm.nih.gov/pubmed/14663118.
Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother. 2011;55(12):5914-5922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911.
TEmAA ANRS 12109 Study Group, Arrive E, Chaix ML, et al. Maternal and nenonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance. AIDS. 2010;24(16):2481-2488. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827166.
Mirochnick M, Taha T, Kreitchmann R, et al. Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and their infants during the first week of life. J Acquir Immune Defic Syndr. 2014;65(1):33-41. Available at http://www.ncbi.nlm.nih.gov/pubmed/23979002.
Gray G, Violari A, McIntyre J, et al. Antiviral activity of nucleoside analogues during short-course monotherapy or dual therapy: its role in preventing HIV infection in infants. J Acquir Immune Defic Syndr. 2006;42(2):169-176. Available at http://www.ncbi.nlm.nih.gov/pubmed/16639342.
Rongkavilit C, van Heeswijk RP, Limpongsanurak S, et al. Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates. J Acquir Immune Defic Syndr. 2002;29(5):455-463. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981361.
Torres SM, Walker DM, Carter MM, et al. Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations. Environ Mol Mutagen. 2007;48(3-4):224-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/17358033.
Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S, Enquete Perinatale Francaise Study G. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS. 2003;17(14):2053-2061. Available at http://www.ncbi.nlm.nih.gov/pubmed/14502008.
Pacheco SE, McIntosh K, Lu M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study. J Infect Dis. 2006;194(8):1089-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/16991083.
Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr. 2007;45(1):43-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/17356471.
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(3):334-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/18398973.
Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med. 2008;359(2):119-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/18525035.
Six Week Extended-Dose Nevirapine Study T, 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(9635):300-313. Available at http://www.ncbi.nlm.nih.gov/pubmed/18657709.
Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010;362(24):2271-2281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554982.
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. 2012;379(9812):221-228. Available at http://www.ncbi.nlm.nih.gov/pubmed/22196945.
Moorthy A, Gupta A, Bhosale R, et al. Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants. PLoS One. 2009;4(1):e4096. Available at http://www.ncbi.nlm.nih.gov/pubmed/19119321.
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(7):911-917. Available at http://www.ncbi.nlm.nih.gov/pubmed/21487249.
Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. 2009;28(3):215-219. Available at http://www.ncbi.nlm.nih.gov/pubmed/19209098.
Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. 2007;21(18):2564-2565. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025905.
McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. 2009;28(12):1127-1129. Available at http://www.ncbi.nlm.nih.gov/pubmed/19820426.
Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. 2011;306(1):70-78. Available at http://www.ncbi.nlm.nih.gov/pubmed/21730243.
Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol or prophylene glycol? 18th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, MA.
Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro effect on bilirubin binding. Pediatr Infect Dis J. 2013;32(9):978-980. Available at http://www.ncbi.nlm.nih.gov/pubmed/23470680.
Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA. 2004;292(2):202-209. Available at http://www.ncbi.nlm.nih.gov/pubmed/15249569.
Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomised clinical trial. Lancet. 2003;362(9391):1171-1177. Available at http://www.ncbi.nlm.nih.gov/pubmed/14568737.
Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. AIDS. 2006;20(9):1281-1288. Available at http://www.ncbi.nlm.nih.gov/pubmed/16816557.
Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. 2005;19(12):1289-1297. Available at http://www.ncbi.nlm.nih.gov/pubmed/16052084.
Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr. 2009;52(3):406-416. Available at http://www.ncbi.nlm.nih.gov/pubmed/19730269.
Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. AIDS. 2009;23(18):2415-2423. Available at http://www.ncbi.nlm.nih.gov/pubmed/19730349.
Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362(24):2282-2294. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554983.
Kesho Bora Study G, de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11(3):171-180. Available at http://www.ncbi.nlm.nih.gov/pubmed/21237718.
Mirochnick M, Dorenbaum A, Blanchard S, et al. Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: association with timing of maternal intrapartum nevirapine dose. J Acquir Immune Defic Syndr. 2003;33(2):153-156. Available at http://www.ncbi.nlm.nih.gov/pubmed/12794547.
Shetty AK, Coovadia HM, Mirochnick MM, et al. Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J Acquir Immune Defic Syndr. 2003;34(5):482-490. Available at http://www.ncbi.nlm.nih.gov/pubmed/14657758.
Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr. 2003;142(1):47-52. Available at http://www.ncbi.nlm.nih.gov/pubmed/12520254.
Mirochnick M, Capparelli E, Connor J. Pharmacokinetics of zidovudine in infants: a population analysis across studies. Clin Pharmacol Ther. 1999;66(1):16-24. Available at http://www.ncbi.nlm.nih.gov/pubmed/10430105.
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(9):655-658. Available at http://www.ncbi.nlm.nih.gov/pubmed/21920159.
Committee on Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics. 2013;131(2):391-396. Available at http://www.ncbi.nlm.nih.gov/pubmed/23359577.
Kuhn L, Reitz C, Abrams EJ. Breastfeeding and AIDS in the developing world. Curr Opin Pediatr. 2009;21(1):83-93. Available at http://www.ncbi.nlm.nih.gov/pubmed/19242244.
Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission of human immunodeficiency virus by breast milk: presumed innocent or presumed guilty? Clin Infect Dis. 1992;15(3):502-507. Available at http://www.ncbi.nlm.nih.gov/pubmed/1445596.
Daar ES. Virology and immunology of acute HIV type 1 infection. AIDS Res Hum Retroviruses. 1998;14 Suppl 3:S229-234. Available at http://www.ncbi.nlm.nih.gov/pubmed/9814948.
Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep. 2005;54(RR-2):1-20. Available at http://www.ncbi.nlm.nih.gov/pubmed/15660015.