Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults

作者：Gallant Joel E; Thompson Melanie; DeJesus Edwin; Voskuhl Gene W; Wei Xuelian; Zhang Heather; White Kirsten; Cheng Andrew; Quirk Erin; Martin Hal

来源：JAIDS: Journal of Acquired Immune Deficiency Syndromes , 2017, 75(1): 61-66.

DOI：10.1097/qai.0000000000001306

<jats:sec>
<jats:title>Objective:</jats:title>
<jats:p>To evaluate antiviral activity, safety, and pharmacokinetics of short-term monotherapy with bictegravir (BIC), a novel, potent HIV integrase strand transfer inhibitor (INSTI).</jats:p>
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<jats:sec>
<jats:title>Design:</jats:title>
<jats:p>Phase 1b, randomized, double-blinded, adaptive, sequential cohort, placebo-controlled study.</jats:p>
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<jats:sec>
<jats:title>Methods:</jats:title>
<jats:p>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 (DAVG<jats:sub>11</jats:sub>) for plasma HIV-1 RNA. HIV-1 RNA, adverse events (AEs), and laboratory assessments were evaluated through day 17.</jats:p>
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<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>Twenty participants were enrolled (n = 4/group). Mean DAVG<jats:sub>11</jats:sub> 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 (<jats:italic toggle="yes">P</jats:italic> &lt; 0.001); mean decreases were 1.45–2.43 log<jats:sub>10</jats:sub> 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 &lt;50 copies/mL by end of study. Median T<jats:sub>max</jats:sub> ranged from 1.0 to 1.8 hours (day 1, postdose) and 1.3–2.7 hours (day 10), with median t<jats:sub>1/2</jats:sub> 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.</jats:p>
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<jats:sec>
<jats:title>Conclusions:</jats:title>
<jats:p>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.</jats:p>
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• 出版日期2017-5-1