Infectious Diseases Unit, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.
Lancet Infect Dis. 2012 Feb;12(2):111-8. doi: 10.1016/S1473-3099(11)70290-0. Epub 2011 Oct 20.
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.
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 μL. 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.
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 87% (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.
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 mg dolutegravir in phase 3 trials.
多替拉韦（S/GSK1349572）是一种新的 HIV-1 整合酶抑制剂，具有每日一次、无需增效剂的抗病毒活性。SPRING-1 是一项正在进行的研究，旨在选择第 3 阶段评估的剂量。我们报告了预先计划的主要和中期分析的数据。
在一项 2b 期、多中心、剂量范围研究中，未经治疗的成年患者被随机分配（1:1:1:1）接受 10mg、25mg 或 50mg 多替拉韦或 600mg 依非韦伦治疗。仅对药物进行盲法，而不对剂量进行盲法。随机分配由中央综合语音应答系统根据计算机生成的代码进行。根据治疗药物是与替诺福韦加恩曲他滨还是阿巴卡韦加拉米夫定联合使用，患者被随机分配到相应的剂量组。我们的研究于 2009 年 7 月 9 日在法国、德国、意大利、俄罗斯、西班牙和美国的 34 个地点进行。符合条件的参与者为 HIV-1 血清阳性，年龄 18 岁或以上，血浆 HIV RNA 病毒载量至少为 1000 拷贝/ml，CD4 计数至少为 200 个/μl。我们的主要终点是第 16 周时病毒载量低于 50 拷贝/ml 的参与者比例，我们报告了第 48 周的数据。分析基于分配组进行，包括接受至少一剂研究药物的所有参与者。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00951015。
205 名患者被随机分配并接受了至少一剂研究药物：53、51 和 51 名患者分别接受 10mg、25mg 和 50mg 多替拉韦治疗，50 名患者接受依非韦伦治疗。病毒载量最多为 50 拷贝/ml 的第 16 周病毒学应答率在所有多替拉韦剂量组（各组之间差异较小）为 93%（144/155 名患者），依非韦伦组为 60%（30/50 名患者）；第 48 周的病毒学应答率在所有多替拉韦剂量组为 87%（139/155 名患者），依非韦伦组为 82%（41/50 名患者）。核苷逆转录酶抑制剂亚组之间的应答率相似。我们在多替拉韦组发现了 3 例病毒学失败，依非韦伦组发现了 1 例，我们没有发现任何整合酶抑制剂突变。我们没有发现任何与剂量相关的临床或实验室毒性作用，依非韦伦组（20%）比多替拉韦组（8%）更多的药物相关不良事件为中重度或更高级别。我们没有判断任何严重不良事件与多替拉韦有关。
多替拉韦每日一次给药，无需增效剂，具有有效的抗病毒活性，且在所有评估剂量下均具有良好的耐受性。我们的研究结果支持在 3 期临床试验中评估每日一次 50mg 多替拉韦。
