St Jude Children's Research Hospital, Memphis, TN, USA.
Joint Clinical Research Centre, Kampala, Uganda.
Lancet HIV. 2016 Dec;3(12):e561-e568. doi: 10.1016/S2352-3018(16)30121-7. Epub 2016 Oct 17.
The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents.
We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per μL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUC) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUC) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775.
Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUC for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUC for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults.
The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children.
Gilead Sciences.
替诺福韦前药阿法韦仑与富马酸替诺福韦二吡呋酯相比，具有改善的肾脏和骨骼安全性。我们旨在评估在感染 HIV 的、未经治疗的青少年中，这种艾维雷格、考比司他、恩曲他滨和阿法韦仑的单片固定剂量复方制剂的安全性、药代动力学和疗效。
我们在南非、泰国、乌干达和美国的十个医院诊所进行了一项 48 周、单臂、开放性标签的试验，纳入了感染 HIV 的、未经治疗的青少年。合格的参与者年龄在 12-18 岁之间，血浆 HIV-1 RNA 至少为 1000 拷贝/ml，CD4 计数至少为 100 个/μL，根据 Schwartz 公式估计肾小球滤过率至少为 90ml/min/1.73m，体重至少为 35kg，以及 HIV-1 基因型对艾维雷格、恩曲他滨和替诺福韦敏感。参与者每天一次服用含有 150mg 艾维雷格、150mg 考比司他、200mg 恩曲他滨和 10mg 阿法韦仑的单一片剂方案，随餐服用（由其父母或照顾者给药）。就诊时间为第 1、2、4、8、12、16、24、32、40 和 48 周。主要终点是艾维雷格的终末剂量间隔（AUC）浓度（AUC）和替诺福韦阿法韦仑的零时间至最后可定量浓度（AUC）的药代动力学参数（AUC）的发生率，治疗出现的严重不良事件，以及治疗开始后出现的所有不良事件（包括骨密度数据）。所有接受一剂研究药物的参与者均纳入主要和安全性分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01854775。
在 2013 年 5 月 22 日至 2014 年 7 月 22 日期间，我们共纳入了 50 名参与者，所有参与者均接受了指定的治疗；24 名参与者参与了强化药代动力学评估。48 名患者完成了 48 周的治疗；两名患者停药（一名在第 8 周时退出，一名在第 12 周时失访）。该方案耐受性良好，无与不良事件相关的停药。艾维雷格的平均 AUC 为 23840ng×h/ml（变异系数[CV]为 25.5%），替诺福韦阿法韦仑的平均 AUC 为 189ng×h/ml（CV 为 55.8%）。有四名参与者（8%）发生严重不良事件，其中一起（中间葡萄膜炎）被认为与研究方案有关，但无需中断治疗即可解决。最常见的与研究药物相关的不良事件是恶心（10 名参与者）、腹痛（6 名参与者）和呕吐（5 名参与者）。艾维雷格、考比司他、恩曲他滨和替诺福韦阿法韦仑方案的暴露与以前在成人中观察到的相似。
艾维雷格、考比司他、恩曲他滨和替诺福韦阿法韦仑方案具有良好的耐受性，并达到了与成人相似的药物血浆药代动力学暴露。尽管与小样本量相比没有可比性，但这些数据支持在感染 HIV 的青少年中使用该方案，并及时在年龄较小的儿童中进行评估。
吉利德科学公司。
