Impact of Low Birth Weight and Prematurity on Neonatal Raltegravir Pharmacokinetics: Impaact P1097.

BACKGROUND: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates. METHODS: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations. RESULTS: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants. CONCLUSIONS: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.

Raltegravir pharmacokinetics in neonates following maternal dosing.

: International Maternal Pediatric Adolescent AIDS Clinical Trials P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data were available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with a median cord blood/maternal delivery plasma raltegravir concentration ratio of 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t1/2 26.6 (range, 9.3-184) hours]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate because raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Subtherapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must also be avoided. Two ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials studies are further investigating the pharmacology of raltegravir in neonates.

Prevalence of HIV among women entering labor who accepted or declined voluntary counseling and testing.

OBJECTIVE: To assess whether there was a difference in HIV seroprevalence between eligible women who declined and those who agreed to participate in a study of voluntary counseling and testing among women entering labor with unknown HIV status in South Africa. METHODS: Anonymous cord blood specimens were collected-as dried blood spots-from all women approached for participation in a cluster-randomized trial. No patient identifiers were included on the cord blood specimens. The dried blood spots were analyzed for HIV antibody via enzyme immunoassay and western blotting. RESULTS: Of 7238 women screened for study participation, 1041 (14.4%) had undocumented HIV status; of these women, 542 were eligible for inclusion and 343 enrolled. Based on 513 evaluable samples, the overall seroprevalence was 13.3% (95% confidence interval [CI], 10.4-16.5), which was similar to the 13.1% (95% CI, 9.7-17.2) seroprevalence among the 343 enrolled women. CONCLUSION: Seroprevalence among eligible women was similar to that among enrolled women, which indicates that study participation did not select for a group with an HIV seroprevalence substantially different from that among women who declined to enroll.

Rapid intrapartum or postpartum HIV testing at a midwife obstetric unit and a district hospital in South Africa.

OBJECTIVE: To compare the prepartum and postpartum feasibility and acceptance of voluntary counseling and rapid testing (VCT) among women with unknown HIV status in South Africa. METHODS: Eligible women were randomized according to the calendar week of presentation to receive VCT either while in labor or after delivery. RESULTS: Of 7238 women approached, 542 (7.5%) were eligible, 343 (63%) were enrolled, and 45 (13%) were found to be HIV infected. The proportions of eligible women who accepted VCT were 66.8% (161 of 241) in the intrapartum arm and 60.5% (182 of 301) in the postpartum arm, and the difference of 6.3% (95% CI, -1.8% to 14.5%) was not significant. The median times (44 and 45 minutes) required to conduct VCT were also similar in the 2 arms. In the intrapartum arm, all women in true labor received their test results before delivery and all those found to be HIV positive accepted prophylaxis with nevirapine before delivery. CONCLUSIONS: Rapid testing in labor wards for women with an unknown HIV status is feasible and well accepted, and allows for a more timely antiretroviral prophylaxis than postpartum testing.