Eley Timothy, Huang Shu-Pang, Conradie Francesca, Zorrilla Carmen D, Josipovic Deirdre, Botes Mariëtte, Osiyemi Olayemi, Hardy Hélène, Bertz Richard, McGrath Donnie
1 Bristol-Myers Squibb, Research and Development , Hopewell, New Jersey.
AIDS Res Hum Retroviruses. 2013 Oct;29(10):1287-92. doi: 10.1089/AID.2013.0002. Epub 2013 Jul 19.
A theoretical concern exists that atazanavir (ATV) use during pregnancy may exacerbate physiologic neonatal hyperbilirubinemia. The aim of this substudy was to evaluate patterns of neonatal bilirubin following ATV/ritonavir (RTV) treatment of pregnant mothers and clinical and pharmacogenetic factors that may correlate. The design involved a subanalysis of study AI424182, a multicenter, open-label, prospective, single-arm Phase I study. The study had two treatment arms: (1) ATV/RTV 300/100 mg once daily or (2) ATV/RTV 400/100 mg once daily, both in combination with zidovudine/lamivudine 300/150 mg twice daily. Total bilirubin was assessed at baseline, each visit, and delivery day for mothers and on days 1 (delivery day), 3, 5, and 7 and weeks 2 and 6 for neonates. Blood samples were obtained for UGT1A1 genotyping and ATV cord blood concentration. Bilirubin elevation of any grade occurred in 14/40 neonates (35%). All Grade 3 to 4 bilirubin abnormalities (n=7) occurred after day 14. The pattern of neonatal bilirubin levels reported was consistent with neonatal physiologic elevations of bilirubin. Little correlation was observed between either maternal bilirubin levels over the last 4 weeks of pregnancy (including delivery) or ATV cord concentration and neonatal bilirubin. There was a significant association between UGT1A1 genotype and bilirubin grade in the maternal population (p=0.0006) but not neonates (p=0.49). Neither neonatal UGT1A1 genotype nor cord blood ATV concentration is a good predictor of neonatal hyperbilirubinemia. ATV/RTV treatment of mothers does not appear to exacerbate neonatal physiologic hyperbilirubinemia.
理论上担心孕期使用阿扎那韦（ATV）可能会加重生理性新生儿高胆红素血症。本亚研究的目的是评估对孕妇进行ATV/利托那韦（RTV）治疗后新生儿胆红素的变化模式以及可能与之相关的临床和药物遗传学因素。该设计涉及对研究AI424182的亚分析，这是一项多中心、开放标签、前瞻性、单臂I期研究。该研究有两个治疗组：（1）ATV/RTV 300/100mg每日一次，或（2）ATV/RTV 400/100mg每日一次，两者均与齐多夫定/拉米夫定300/150mg每日两次联合使用。在基线、每次访视和母亲分娩日以及新生儿出生第1天（分娩日）、第3天、第5天、第7天以及第2周和第6周评估总胆红素。采集血样进行UGT1A1基因分型和ATV脐血浓度检测。14/40例新生儿（35%）出现任何级别的胆红素升高。所有3至4级胆红素异常（n = 7）均发生在第14天之后。报告的新生儿胆红素水平模式与新生儿生理性胆红素升高一致。在妊娠最后4周（包括分娩）期间母亲的胆红素水平或ATV脐血浓度与新生儿胆红素之间几乎未观察到相关性。在母亲群体中，UGT1A1基因型与胆红素分级之间存在显著关联（p = 0.0006），但在新生儿中无此关联（p = 0.49）。新生儿UGT1A1基因型和脐血ATV浓度均不是新生儿高胆红素血症的良好预测指标。对母亲进行ATV/RTV治疗似乎不会加重新生儿生理性高胆红素血症。
