Predicting Long-Term Survival Without Major Disability for Infants Born Preterm.

OBJECTIVE: To describe the long-term neurodevelopmental and cognitive outcomes for children born preterm. STUDY DESIGN: In this retrospective cohort study, information on children born in Western Australia between 1983 and 2010 was obtained through linkage to population databases on births, deaths, and disabilities. For the purpose of this study, disability was defined as a diagnosis of intellectual disability, autism, or cerebral palsy. The Kaplan-Meier method was used to estimate the probability of disability-free survival up to age 25 years by gestational age. The effect of covariates and predicted survival was examined using parametric survival models. RESULTS: Of the 720 901 recorded live births, 12 083 children were diagnosed with disability, and 5662 died without any disability diagnosis. The estimated probability of disability-free survival to 25 years was 4.1% for those born at gestational age 22 weeks, 19.7% for those born at 23 weeks, 42.4% for those born at 24 weeks, 53.0% for those born at 25 weeks, 78.3% for those born at 28 weeks, and 97.2% for those born full term (39-41 weeks). There was substantial disparity in the predicted probability of disability-free survival for children born at all gestational ages by birth profile, with 5-year estimates of 4.9% and 10.4% among Aboriginal and Caucasian populations, respectively, born at 24-27 weeks and considered at high risk (based on low Apgar score, male sex, low sociodemographic status, and remote region of residence) and 91.2% and 93.3%, respectively, for those at low risk (ie, high Apgar score, female sex, high sociodemographic status, residence in a major city). CONCLUSIONS: Apgar score, birth weight, sex, socioeconomic status, and maternal ethnicity, in addition to gestational age, have pronounced impacts on disability-free survival.

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.