优化危重患者的能量供应
作者 ： Claudia Paula Heidegger ,Mette M Berger ,Séverine Graf ,Walter Zingg ,Patrice Darmon ,Michael C Costanza期刊名称：柳叶刀杂志(Lancet)
发表时间：2012-12-03
索引：Lancet.2012 Dec 3;
得特格韦（S/GSK1349572）是一种每日一次给药的HIV整合酶抑制剂，是一种具有强效抗病毒活性的安全的制剂。本文的研究者比较了得特格韦和同为HIV整合酶抑制剂的雷特格韦作为初次接受系统治疗的HIV-1感染的患者群体的疗效，Francois Raffi等代表SPRING-2研究小组的研究成员将上述研究的结果发表在Lancet 2013年1月最新的在线期刊上。
SPRING-2研究是一个为期96周的3期随机、双盲、阳性对照、非劣效性研究，研究开始于2010年10月19日，研究在分布于加拿大、美国、澳大利亚和欧洲的100个中心内进行。患者的入组标准为：年龄在18岁及以上的既往没有接受过系统治疗的HIV-1感染的患者、HIV-1 RNA浓度在1000拷贝/mL及以上，研究者按照经由电脑生成的随机序列将这些患者按照1:1的比例随机分为两组，一组接受每日一次、每次50mg的得特格韦治疗，另一组接受每日两次、每次400mg的雷特格韦治疗。在本研究中，研究药物和替诺福韦/恩曲他滨或阿巴卡韦/拉米夫定共同给药。根据HIV-1 RNA的筛查结果(≤100 000 拷贝/mL或>100 000拷贝/mL)和核苷酸逆转录酶抑制剂种类对患者进行随机化分层。在随机化分组之前，研究者就知道了患者HIV-1 RNA的检测结果。研究的主要终点是在第48周时，血HIV-1 RNA在50拷贝/mL以下、有10%非劣效性界值的患者所占的比例。研究的次要终点包括CD4细胞计数与基线相比的变化、不良反应的发生率和严重程度、患者实验室指标的变化情况以及耐药情况出现的基因型和表型证据。研究者主要采用意向治疗对研究进行分析。本研究在ClinicalTrials.gov进行注册，注册号为NCT01227824。
有411名受试者被随机分入得特格韦组，另有411名患者分入雷特格韦组，这些患者至少接受一个治疗剂量的药物。在研究的第48周时，得特格韦组中有88%的患者达到了HIV-1 RNA小于50拷贝/mL，在雷特格韦组中上述患者的比例为85%，调整后的差异为2.5%，95%可信区间为2.2至7.1。不良反应事件的发生率在两组间相似。最常见的不良反应事件为恶心（得特格韦组为14%，雷特格韦组为13%）、头痛（得特格韦组为12%，雷特格韦组为12%）、鼻咽炎（得特格韦组为11%，雷特格韦组为12%）和腹泻（两组均为11%）。几乎没有患者发生与药物相关的严重不良反应，两组分别为3人和5人，比例皆小于1%，同时，也几乎没有不良反应事件导致患者终止治疗，两组分别为10人和7人，所占比例都为2%。在两个治疗组中，CD4 细胞计数与基线相比平均增加230细胞/μL。分级实验室毒性反应在两组间的发生率相似。研究者注意到没有证据显示得特格韦组中的患者在治疗过程中出现抗病毒治疗失败，而雷特格韦组内接受抗病毒治疗失败的患者中，有1名患者（6%）出现对整合酶的耐药，有4名患者（21%）出现对核苷酸逆转录酶抑制剂耐药。
本研究结果提示，与雷特格韦相比，得特格韦的治疗效果和安全性并不劣于前者，这意味着，如果上述结果得到最终证实的话，每日一次得特格韦联合固定剂量的核苷酸逆转录酶抑制剂对于既往没有接受过系统治疗的HIV-1感染患者而言是一种有效的新的治疗选择。
Lancet. 2013 Jan 7. pii: S0140-6736(12)61853-4. doi: 10.1016/S0140-6736(12)61853-4.
Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study.
Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, Bloch M, Podzamczer D, Pokrovsky V, Pulido F, Almond S, Margolis D, Brennan C, Min S; on behalf of the SPRING-2 study group.
SourceUniversity of Nantes, Nantes, France. Electronic address: francois.raffi@wanadoo.fr.
Abstract
BACKGROUND: Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.
METHODS: SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 copies per mL or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824.
FINDINGS: 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 patients in the dolutegravir group vs 53 in the raltegravir group), headache (51 vs 48 ), nasopharyngitis (46 vs 48 ), and diarrhoea (47 in each group). Few patients had drug-related serious adverse events (three [<1%] vs five ), and few had adverse events leading to discontinuation (ten vs seven in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.
INTERPRETATION: The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.
FUNDING: ViiV Healthcare.
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