Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.
Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults.
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DOI：
10.1097/qai.0000000000001306
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Martin H
中科院分区：
文献类型：
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作者：
Gallant JE;Thompson M;DeJesus E;Voskuhl GW;Wei X;Zhang H;White K;Cheng A;Quirk E;Martin H
评估bictegravir （BIC）短期单药治疗的抗病毒活性、安全性和药代动力学，bictegravir是一种新型、有效的HIV整合酶链转移抑制剂（INSTI）。1b期，随机、双盲、适应性、序贯队列、安慰剂对照研究。未接受抗逆转录病毒治疗的hiv感染成人随机接受BIC（5、25、50或100 mg）或安慰剂，每天一次，持续10天。主要终点是血浆HIV-1 RNA从基线到第11天的时间加权平均变化（DAVG11）。在第17天对HIV-1 RNA、不良事件（ae）和实验室评估进行评估。20名参与者入组（n = 4/组）。BIC剂量组的平均DAVG11范围为- 0.92至- 1.61，而安慰剂组为- 0.01。与安慰剂相比，所有BIC剂量的血浆HIV-1 RNA在第11天较基线显著降低（P < 0.001）；平均减少1.45-2.43 log10拷贝/mL。在第11天，BIC暴露增加与血浆HIV-1 RNA较基线的减少增加相关。三名服用BIC（50或100 mg）的参与者在研究结束时血浆HIV-1 RNA <50拷贝/mL。中位Tmax为1.0 ~ 1.8小时（给药后第1天）和1.3 ~ 2.7小时（第10天），中位t1/2为15.9 ~ 20.9小时。到第17天，没有参与者出现原发性inri - r替代。BIC耐受性良好，没有因不良事件而停药。BIC是一种新型的、有效的、未增强的INSTI，在单药治疗10天后，HIV-1 RNA显示出快速的、剂量依赖性的下降。BIC耐受性良好，在hiv感染者中表现出快速吸收和每日一次治疗的半衰期支持。
To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI). Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study. HIV-infected adults not taking antiretroviral therapy were randomized to receive BIC (5, 25, 50, or 100 mg) or placebo once daily for 10 days. Primary endpoint was time-weighted average change from baseline to day 11 (DAVG11) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17. Twenty participants were enrolled (n = 4/group). Mean DAVG11 ranged from −0.92 to −1.61 across BIC doses versus −0.01 for placebo. Significant reductions in plasma HIV-1 RNA from baseline at day 11 were observed for all BIC doses compared with placebo (P < 0.001); mean decreases were 1.45–2.43 log10 copies/mL. Increased BIC exposures correlated with increased reduction in plasma HIV-1 RNA from baseline on day 11. Three participants on BIC (50 or 100 mg) achieved plasma HIV-1 RNA <50 copies/mL by end of study. Median Tmax ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3–2.7 hours (day 10), with median t1/2 ranging from 15.9 to 20.9 hours. No participant developed primary INSTI-R substitution through day 17. BIC was well tolerated, with no discontinuations because of adverse events. BIC is a novel, potent, unboosted INSTI that demonstrated rapid, dose-dependent declines in HIV-1 RNA after 10 days of monotherapy. BIC was well tolerated, and displayed rapid absorption and a half-life supportive of once-daily therapy in HIV-infected subjects.