Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Seattle Children's Hospital, Seattle, WA.
Hepatology. 2017 Aug;66(2):371-378. doi: 10.1002/hep.28995. Epub 2017 Jun 19.
No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir.
Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).
未批准用于慢性丙型肝炎病毒（HCV）感染儿童的全口服、直接作用抗病毒方案。我们进行了一项 2 期、多中心、开放标签研究，以评估 ledipasvir-索磷布韦在慢性 HCV 基因型 1 感染的青少年中的疗效和安全性。100 名 12-17 岁的患者接受了每日一次的 90mg ledipasvir 和 400mg 索磷布韦联合片剂治疗 12 周。在开始给药后的第 10 天，10 名患者进行了索磷布韦、ledipasvir 和索磷布韦代谢物 GS-331007 的强化药代动力学评估。主要疗效终点是治疗后 12 周时持续病毒学应答的患者百分比。患者的中位年龄为 15 岁（范围 12-17 岁）。大多数（80%）患者为 HCV 初治患者，84%为围产期传播感染。1 名患者患有肝硬化，42 名患者无肝硬化；57 名患者的纤维化程度未知。总体而言，98%（98/100；95%置信区间 93%-100%）的患者在 12 周时达到持续病毒学应答。无患者发生病毒学失败。2 名未在 12 周时达到持续病毒学应答的患者在治疗期间或之后失访。最常见的报告不良事件为头痛（27%的患者）、腹泻（14%）和疲劳（13%）。未报告严重不良事件。与 ledipasvir 和索磷布韦 2 期和 3 期研究中的成年人相比，索磷布韦、ledipasvir 和 GS-331007 的浓度-时间曲线下面积（tau）和最大浓度值在 50%-200%的预设药代动力学等效范围内。
ledipasvir-索磷布韦对慢性 HCV 基因型 1 感染的青少年非常有效；目前用于成年人的 ledipasvir-索磷布韦剂量在青少年中耐受良好，具有适当的药代动力学特征。（《肝脏病学》2017；66:371-378）
