Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial
Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial
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DOI：
10.1016/s1473-3099(11)70290-0
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发表时间：
2012-02-01
影响因子：
56.3
通讯作者：
Min, Sherene
中科院分区：
文献类型：
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作者：
van Lunzen, Jan;Maggiolo, Franco;Min, Sherene
背景Dolutegravir（S/GSK 1349572）是一种新的HIV-1整合酶抑制剂，每日一次，未加强剂量，具有抗病毒活性。SPRING-1是一项正在进行的研究，旨在选择III期评估的剂量。我们目前的数据从预先计划的主要和中期analysis.Methods在2b期，多中心，剂量范围研究，治疗初治成人随机分配（1：1：1：1）接受10毫克，25毫克，或50毫克度鲁特韦或600毫克依法韦仑。对剂量但非药物分配设盲。根据计算机生成的代码，通过中央集成语音应答系统进行随机化。研究药物给予替诺福韦加恩曲他滨或阿巴卡韦加拉米夫定。我们的研究于2009年7月9日开始在法国、德国、意大利、俄罗斯、西班牙和美国的34个研究中心进行。合格的参与者为HIV-1血清阳性，年龄≥ 18岁，血浆HIV RNA病毒载量至少为1000拷贝/mL，CD 4计数至少为200个细胞/μ L。我们的主要终点是第16周病毒载量低于50拷贝/mL的参与者比例，我们提供了第48周的数据。基于分配组进行分析，包括至少接受一剂研究药物的所有受试者。该研究注册于ClinicalTrials.gov，编号NCT 00951015。结果205名患者被随机分配并接受至少一剂研究药物：53、51和51名分别接受10 mg、25 mg和50 mg dolutegravir，50名接受依法韦仑。第16周，所有剂量的度鲁特韦（剂量组之间差异不大）对病毒载量最多为50拷贝/mL的应答率为93%（144/155名参与者），依法韦仑为60%（30/50）;第48周，所有剂量的度鲁特韦为90%（139/155），依法韦仑为82%（41/50）。核苷类逆转录酶抑制剂亚组之间的缓解率相似。我们在度鲁特韦组和依法韦仑组分别发现了3例和1例病毒学失败，我们没有发现任何整合酶抑制剂突变。我们没有发现任何剂量相关的临床或实验室毒性反应，依法韦仑组（20%）比度鲁特韦组（8%）有更多的中度或更高强度的药物相关不良事件。我们没有判断任何严重的不良事件与dolutegravir.Interpretation相关，Dolutegravir在每日一次给药时有效，无需药代动力学增强剂，并且在所有评估剂量下耐受性良好。我们的研究结果支持在3期试验中每天一次50 mg dolutegravir的评估。
Background Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses.Methods In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per mu L. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015.Findings 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 90% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir.Interpretation Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 rug dolutegravir in phase 3 trials.