多替拉韦在经治的HIV-1感染青少年中的安全性、药代动力学及疗效：IMPAACT P1093研究的48周结果

Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093.

作者信息

Viani Rolando M, Alvero Carmelita, Fenton Terry, Acosta Edward P, Hazra Rohan, Townley Ellen, Steimers Debra, Min Sherene, Wiznia Andrew

机构信息

From the *Department of Pediatrics, University of California, San Diego, California; †Rady Children's Hospital San Diego, La Jolla, California; ‡Statistical and Data Analysis Center, Harvard School Public Health, Boston, Massachusetts; §University of Alabama at Birmingham, Birmingham, Alabama; ¶Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; ‖HJF-DAIDS, A Division of the Henry Jackson Foundation, Contractor to the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; **GlaxoSmithKline, Research Triangle Park, North Carolina; and ††Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York.

出版信息

Pediatr Infect Dis J. 2015 Nov;34(11):1207-13. doi: 10.1097/INF.0000000000000848.

DOI:10.1097/INF.0000000000000848

PMID:26244832

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4604048/

Abstract

OBJECTIVE

To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment-experienced adolescents.

METHODS

Children older than 12 to younger than 18 years received dolutegravir weight-based fixed doses at approximately 1.0 mg/kg once daily in a phase I/II multicenter open label 48-week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through week 48.

RESULTS

Twenty-three adolescents were enrolled and 22 (96%) completed the 48-week study visit. Median age and weight were 15 years and 52 kg, respectively. Median [interquartile range (IQR)] baseline CD4+ cell count was 466 cells/μL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC0-24) and 24 hour postdose concentration (C24) were 46.0 μg hours/mL and 0.90 μg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA <400 copies/mL was achieved in 74% [95% confidence interval (CI): 52-90%] at week 48. Additionally, 61% (95% CI: 39-80%) had an HIV RNA <50 copies/mL at week 48. Median (IQR) gain in CD4 cell count at week 48 was 84 cells/μL (-81, 238). Dolutegravir was well tolerated, with no grade 4 adverse events, serious adverse events or discontinuations because of serious adverse events.

CONCLUSIONS

Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48.

摘要

目的

评估多替拉韦联合优化背景治疗方案在有治疗经验的HIV感染青少年中的药代动力学（PK）、安全性和疗效。

方法

在一项I/II期多中心开放标签48周研究中，年龄在12岁以上至18岁以下的儿童接受基于体重的多替拉韦固定剂量，约1.0 mg/kg，每日一次。在将多替拉韦添加到失败方案中或在治疗中断结束时开始给药后，在稳态时进行强化PK评估。在第48周进行安全性、HIV RNA和CD4细胞计数评估。

结果

23名青少年入组，22名（96%）完成了48周的研究访视。中位年龄和体重分别为15岁和52 kg。基线CD4+细胞计数的中位数[四分位间距（IQR）]为466个细胞/μL（297，771）。基线HIV-1 RNA log10的中位数（IQR）为4.3 log10拷贝/mL（3.9，4.6）。从给药时间到给药后24小时的血浆浓度-时间曲线下面积（AUC0-24）和给药后24小时浓度（C24）的多替拉韦几何平均值分别为46.0 μg·小时/mL和0.90 μg/mL，根据成人PK范围，这些值在研究目标范围内。在第48周时，74%[95%置信区间（CI）：52-90%]的患者实现了HIV RNA<400拷贝/mL的病毒学成功。此外，在第48周时，61%（95%CI：39-80%）的患者HIV RNA<50拷贝/mL。第48周时CD细胞计数增加的中位数（IQR）为84个细胞/μL（-81，238）。多替拉韦耐受性良好，无4级不良事件、严重不良事件或因严重不良事件导致的停药。