JAIDS Journal of Acquired Immune Deficiency Syndromes:
Nevirapine Concentrations in Newborns Receiving an Extended Prophylactic Regimen
Mirochnick, Mark MD*; Nielsen-Saines, Karin MD, MPH†; Pilotto, Jose Henrique MD, DST‡; Pinto, Jorge MD, DSc§; Jiménez, Eleanor MD∥; Veloso, Valdilea G MD¶; Parsons, Teresa PhD#; Watts, D Heather MD**; Moye, Jack MD**; Mofenson, Lynne M MD**; Camarca, Margaret RN, MPH††; Bryson, Yvonne MD†; and the NICHD/HPTN 040/PACTG 1043 Protocol Team
From the *Department of Pediatrics, Boston University School of Medicine, Boston, MA; †Department of Pediatrics, David Geffen University of California Los Angeles School of Medicine, Los Angeles, CA; ‡Department of Sexually Transmitted Diseases, Hospital Geral de Nova Iguaçu, Nova Iguaçu, Brazil; §Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil; ∥Department of Pediatrics, San Juan City Hospital, San Juan, PR; ¶Instituto de Pesquisa Clínica Evandro Chagas/Fundacao Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; #Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD; **Pediatric, Adolescent and Maternal AIDS Branch, National Institute of Child Health and Human Development (NICHD)/National Institutes of Health, Bethesda, MD; and ††Westat, Inc., Rockville, MD.
Received for publication March 7, 2007; accepted October 22, 2007.
Funded by the NICHD (contract NO1-HD33345) and cosponsored by the HIV Prevention Trials Network (HPTN), the Pediatric AIDS Clinical Trials Group (PACTG), and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group.
Presented in part at the 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 6, 2006.
Correspondence to: Mark Mirochnick, MD, Boston Medical Center, 91 East Concord Street, 6th Floor, Boston, MA 02118 (e-mail: firstname.lastname@example.org).
Background: The optimal neonatal antiretroviral (ARV) regimen for prevention of HIV mother-to-child transmission (MTCT) is unknown for infants born to mothers who receive no ARVs during pregnancy.
Methods: As part of a protocol comparing the efficacy of 3 neonatal ARV regimens in preventing HIV-1 MTCT in neonates born to mothers who receive no prenatal treatment with ARVs, we devised a 3-dose nevirapine (NVP) regimen with the goal of maintaining the NVP plasma concentration >100 ng/mL (10 times the in vitro median inhibitory concentration of 10 ng/mL) during the first 2 weeks of life. NVP concentrations were measured in 14 newborns participating in a pharmacokinetics substudy during the second week of life and in single samples from 30 more newborns on day 10 to 14.
Results: The median NVP elimination half-life was 30.2 hours (range: 17.8 to 50.3 hours). The NVP concentration remained greater than the target of 100 ng/mL in all samples collected through day 10 of life. By day 14, more than half of the newborns in the pharmacokinetic substudy had NVP levels <100 ng/mL, although only 1 neonate had no detectable NVP.
Conclusion: Although this regimen failed to meet our 100-ng/mL target, it did maintain detectable NVP concentrations in nearly all newborns through the end of the second week of life and is to be used in the parent efficacy protocol.
Mother-to-child transmission (MTCT) of HIV has been dramatically reduced with the use of antiretrovirals (ARVs) administered to the mother during pregnancy and labor and to the neonate after birth.1,2 If the mother does not receive ARV treatment during pregnancy, however, the optimal composition and duration of postnatal neonatal ARV prophylaxis is unknown. As part of a protocol comparing the efficacy of 3 different ARV regimens in preventing transmission in such newborns (the National Institute of Child Health and Human Development [NICHD] HIV Prevention Trials Network [HPTN] 040/Pediatric AIDS Clinical Trials Group [PACTG] 1043 study), we devised an neonatal nevirapine (NVP) regimen with the goal of maintaining the neonatal NVP plasma concentration >100 ng/mL, 10 times the in vitro median inhibitory concentration (IC50) of 10 ng/mL, throughout the first 2 weeks of life using a minimal number of NVP doses. This report describes NVP concentrations during the second week of life in neonates receiving this regimen.
The NICHD HPTN 040/PACTG 1043 study is a multicenter 3-arm efficacy study in babies born to HIV-infected women who had not received any ARV treatment before labor. The 3 regimens being studied are 6 weeks of zidovudine (ZDV) alone (control arm), 6 weeks of ZDV plus lamivudine/nelfinavir for 2 weeks, and 6 weeks of ZDV plus 3 doses of NVP during the first week of life. Newborns in the NVP arm received 3 12-mg NVP doses (8 mg per dose if the newborn's birth weight was ≤2000 g): 1 dose each at 0 to 2, 2 to 4, and 6 to 8 days of life. The primary objective of the study is to compare the efficacy, safety, and tolerance of the 3 regimens and the enrollment target is 1731 babies. Eligible neonates were <48 hours old at the time of enrollment and were born to mothers who were identified as HIV-infected (usually at the time of delivery) and received no ARV prophylaxis during their pregnancy. Their mothers may have received oral or intravenous ZDV during labor. Exclusion criteria included gestational age <32 weeks, birth weight <1500 g, presence of life-threatening conditions, inability to take oral medication throughout the first 48 hours of life, and administration to the mother of any ARV other than ZDV during labor and delivery. All babies in the study are formula-fed.
Three of the sites participating in the study (Hospital Geral de Nova Iguaçu, Rio de Janeiro, Brazil; Federal University of Minas Gerais, Belo Horizonte, Brazil; and San Juan City Hospital, San Juan, PR) elected to participate in an NVP pharmacokinetics substudy. The main study and substudy were approved by the institutional review boards (IRBs) at all participating institutions, the IRB of the US Principal Investigator, and the Brazilian national IRB (CONEP). Written informed consent was obtained from all women enrolling in the main study, and a separate written informed consent form was obtained for participation in this substudy. Fourteen newborns were enrolled in the substudy and had plasma samples for NVP assay collected before the third NVP dose (administered on day 6 to 8 of life), and then at 4 hours, 24 hours, 3 to 5 days, and 7 days after the dose. To characterize the range of NVP concentrations at the end of the second week of life better, the study protocol also included an assay for NVP concentration of single plasma aliquots collected from an additional 30 newborns during routine study blood drawing at the study visit from day 10 to 14 of life.
NVP plasma concentrations were measured by a validated high-performance liquid chromatography (HPLC) assay with a lower limit of detection of 25 ng/mL.2 Pharmacokinetic calculations were performed using WinNonlin (Pharsight Corporation, Mountain View, CA) and Excel (Microsoft Corporation, Redmond, WA). The NVP concentration target was to maintain a plasma NVP concentration >100 ng/mL through the end of the second week of life.
NVP concentration data were available from 44 neonates born at a median gestational age of 39 weeks (range: 35 to 41 weeks) with a median birth weight of 3035 g (range: 1720 to 3760 g). Maternal median age at delivery was 27 years (range: 18 to 48 years), and median delivery HIV viral load and CD4 cell count were 23,916 copies/mL (range: 121 to 499,362 copies/mL) and 379 cells/mm3 (87 to 1967 cells/mm3), respectively.
In the 14 newborns in the pharmacokinetics substudy, the median NVP concentration just before the third NVP dose on day 6 to 8 of life was 362 ng/mL (range: 165 to 1728 ng/mL). After the dose, median (range) pharmacokinetic parameters were: time to peak concentration (Tmax) = 4 hours (range: 4 to 25 hours), peak concentration (Cmax) = 2286 ng/mL (range: 1241 to 3811 ng/mL), and elimination half-life (t½) = 30.2 hours (range: 17.8 to 50.3 hours). The 3- to 5-day postdose samples were collected at a median age of 10 days (range: 9 to 12 days) and had a median NVP concentration of 459 ng/mL (range: 73 to 1747 ng/mL). The 7-day postdose samples were obtained at a median age of 14 days (range: 13 to 15 days) and had a median NVP concentration of 76 ng/mL (range: <25 to 652 ng/mL). The NVP concentration in the 7-day postdose samples was lower than the assay limit of quantitation of 25 ng/mL in 1 newborn, between 25 and 100 ng/mL in 9 newborns, and >100 ng/mL in 4 newborns (Fig. 1).
The additional 30 samples collected at the day 10 to 14 study visit were obtained at a median age of 11 days (range: 10 to 14 days). The median NVP concentration was 217 ng/mL (range: <25 to 958 ng/mL) and was lower than the assay limit of quantitation in 3 newborns, between 25 and 100 mg/mL in 4 newborns, and >100 ng/mL in 23 newborns (Fig. 2). NVP concentrations from the pharmacokinetics substudy and single-sample subjects plotted against newborn age on the day of collection. The NVP concentration exceeded 100 ng/mL in all samples collected through day 10 of life.
When HIV-infected mothers are identified early in pregnancy, maternal treatment with combination ARV therapy/prophylaxis during pregnancy followed by 6 weeks of infant ZDV prophylaxis after birth can reduce the rate of HIV transmission to <2%.1 HIV infection is often diagnosed in women who receive late or no prenatal care with rapid HIV tests near the end of the pregnancy or during labor, however, after it is too late to begin maternal ARV therapy.3 Data from observational and randomized studies suggest that intrapartum and postnatal infant ARV therapy is effective in reducing HIV infection rates for those infants born to HIV-infected women who did not receive treatment during pregnancy.4-8 Although these studies have demonstrated that the use of a 6-week course of ZDV, single-dose NVP, and single-dose NVP in combination with 1 week of ZDV given to the baby soon after birth can reduce the risk of infection in these infants, the optimal composition and duration of postnatal neonatal ARV prophylaxis for such infants is unknown.4-7
Given the lack of conclusive data supporting the use of alternative regimens, the current standard of care for women identified as being infected with HIV-1 during labor or the early postpartum period in Brazil and in the United States is implementation of intravenous ZDV in the mother during labor, if possible, and 6 weeks of ZDV prophylaxis in the infant, with counseling to forego or suspend breast-feeding.9,10 There are currently no data to address whether additional ARV drugs might provide enhanced safety and efficacy for prevention of MTCT when only infant ARV prophylaxis can be provided and 6 weeks of infant ZDV prophylaxis is given. The goal of the parent protocol of this substudy is to determine if 2 weeks of exposure to NVP or to lamivudine and nelfinavir in addition to 6 weeks of postnatal ZDV is superior to 6 weeks of postnatal ZDV alone in reducing HIV transmission in a non-breast-feeding population. The reasons for limiting infant exposure to NVP, lamivudine, and nelfinavir to 2 weeks when combined with 6 weeks of ZDV prophylaxis are several. The optimal duration of infant prophylaxis to prevent MTCT is not known; recommended postexposure prophylaxis of HIV exposure in adults is limited to 4 rather than 6 weeks.11 In a meta-analysis by Dunn et al,12 93% of newborns with perinatal HIV infection in non-breast-feeding populations had HIV detectable by 2 weeks of age, indicating that most intrapartum HIV transmission has occurred by the age of 2 weeks. Finally, there is the need to minimize the expense and complexity of regimens to make them more practical in resource-sparse settings and a desire to limit toxicity in infants. For these reasons, exposure to ARVs in addition to the infant 6-week ZDV regimen was limited to the first 2 weeks of prophylaxis.
For women presenting late in labor (in high- and low-income countries), it is crucial to determine which ARV regimen for the infant is most effective and safest in preventing intrapartum acquisition of HIV. If the results of the parent study demonstrate superior efficacy in prevention of intrapartum HIV perinatal transmission with short-course combination ARV therapy to the infant, an additional and more effective strategy than the 6-week infant ZDV regimen for prevention of MTCT when the mother does not receive ARV drugs is going to be made available. ARV prophylaxis to infants alone may save valuable health care resources, because ARV dose size is considerably smaller when dosing infants rather than mothers. In addition, dosing the infant rather than the mother avoids maternal single-dose NVP exposure and the potential for the development of maternal NVP resistance in the mother, although infected infants may develop NVP resistance.
Our goal in this substudy was to determine if the modified NVP dosing regimen maintained NVP concentrations greater than the target of 100 ng/mL through the end of the second week of life. We chose to use standardized dosing by weight bands (12 mg if birth weight >2000 g, 8 mg if birth weight ≤2000 g) rather than dosing on an individual per-kilogram basis to facilitate study implementation across sites, to simplify drug administration to enrolled newborns, and to make the results more easily transferable to a variety of settings once the optimum regimen is determined. Previous phase 1 studies of the HIV Network (HIVNET) 012 NVP regimen of 1 dose to the mother during labor and another to the neonate after birth demonstrated that this 2-dose mother-neonate regimen maintained NVP concentrations >100 ng/mL through the end of the first week of life.13,14 Because the mothers of the newborns in the current study did not receive NVP during labor, we gave an initial newborn dose within 48 hours of birth to replace the absent maternal intrapartum dose and a second newborn dose as per the HIVNET 012 regimen, and we then added a third NVP dose at around 1 week of age. The NVP concentration before the administration of the third dose was >100 ng/mL in all newborns in the pharmacokinetics substudy, consistent with the prior phase 1 studies. After administration of the third dose, NVP levels remained greater than the target of 100 ng/mL in all newborns through 10 days of life. By day 14, more than half of the newborns in the pharmacokinetic substudy had NVP levels <100 ng/mL, although only 1 newborn had no NVP detectable.
Although the study regimen did not meet our target of keeping the NVP plasma concentration >100 ng/mL through the end of the second week of life, we think it is still adequate for use in the parent efficacy protocol. No data are available to indicate the minimum duration or magnitude of NVP exposure required to minimize intrapartum transmission of HIV when used in combination with ZDV. Although NVP concentrations fell to lower than 100 ng/mL in most newborns by 14 days of life, all had NVP levels >100 ng/mL through day 10 and 71% of newborns at 14 days of life maintained NVP concentrations greater than the assay limit of quantification of 25 ng/mL, which is 2.5 times the IC50 of wild-type virus for NVP. To meet the 100-ng/mL target through the end of the second week of life, a fourth NVP dose would have to be given at around day 10 of life. The cost and difficulty of administering this dose in low-income areas during the second week of life outweigh any likely additional benefit. Administration of additional NVP dosing could increase the risk of development of HIV resistance to NVP in those babies who go on to become infected despite prophylaxis. Thus, in the absence of any data defining a minimum NVP concentration necessary for prevention of HIV infection, we have decided to continue use of the 3-dose NVP regimen combined with 6 weeks of infant ZDV in the parent efficacy study, as approved by the parent study Data Safety and Monitoring Board. The efficacy of this regimen for the prevention of HIV-1 MTCT is to be determined when the parent study is completed.
The authors thank the patients and their families who enrolled in this trial. In addition to the authors, members of the NICHD/HPTN 040/PACTG 1043 Protocol Team include Mariza Morgado, PhD (Departmento de Immunologia-IOC/FIOCRUZ, Rio de Janeiro, Brazil), Eunice Yu (Westat, Rockville, MD), James Bethel, PhD (Westat), Elizabeth Hawkins, AA (Social and Scientific Systems, Silver Spring, MD), Elizabeth Smith, MD (National Institute of Allergy and Infectious Diseases [NIAID], Bethesda, MD), Sheryl Zwerski, RN (NIAID), Marita D. McDonough, RN (Boehringer-Ingelheim Pharmaceuticals, Ridgefield, CT), Charles T. Lancaster (GlaxoSmithKline, Research Triangle Park, NC), Cristina PharoRuth (GlaxoSmithKline), and Ruth E. Dickover, PhD (University of California Los Angeles School of Medicine, Los Angeles, CA). The following investigators also participated in this study: Fabiana Kakehasi, MD, Flávia Ferreira, MD, Lilian Diniz, MD, and Maria Tavares, RN, Federal University of Minas Gerais, Belo Horizonte, Brazil; and Jorge Eurico Ribeiro, MD, Ivete Matins Gomes, MD, and Andrea Gouveia, RN, Hospital Geral de Nova Iguaçu, Nova Iguaçu, Brazil.
Boehringer-Ingelheim Pharmaceuticals supplied the NVP used in this study.
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mother-to-child HIV transmission; neonate; nevirapine; pharmacokinetics
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