Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial
Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial
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DOI：
10.1016/s1473-3099(14)70782-0
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发表时间：
2014-07-01
影响因子：
56.3
通讯作者：
Piontkowsky, David
中科院分区：
文献类型：
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作者：
Arribas, Jose R.;Pialoux, Gilles;Piontkowsky, David
接受抗逆转录病毒治疗的HIV患者可能受益于简化方案，以减少药丸负担和给药频率。本研究旨在评估简化利托那韦增强蛋白酶抑制剂和恩曲他滨联合富马酸替诺福韦二异丙酯治疗病毒学抑制的成人HIV感染的安全性和有效性方法策略-PI是一个96周，国际，多中心，随机，开放标签，在一项3b期试验中，血浆HIV-1 RNA病毒载量低于50拷贝/mL至少6个月的HIV感染成人，正在服用利托那韦增强的蛋白酶抑制剂与恩曲他滨加替诺福韦，随机分配（2：1）转换为联合制剂埃替拉韦、可比司他、恩曲他滨和替诺福韦或继续其现有方案。关键合格标准包括无病毒学失败史，对恩曲他滨和替诺福韦无耐药性，肌酐清除率≥ 70 mL/min。参与者和研究者均未对组分配设盲。主要终点是第48周时病毒载量低于50拷贝/mL的受试者比例，基于美国食品药品监督管理局针对改良意向治疗人群的快照算法，排除了重大方案违背（禁止耐药或基线时未接受蛋白酶抑制剂）。我们预先规定了12%的非劣效性;如果确定了非劣效性，则按照预先规定的序贯检验程序检验优效性。该试验在ClinicalTrials.gov注册，编号NCT 01475838。结果在2011年12月12日至2012年12月20日期间，433名参与者被随机分配并接受至少一剂研究药物。在这些参与者中，293名被分配转换为简化方案（转换组），140名保持现有方案（无转换组）;排除后，分别有290名和139名参与者在修改的意向治疗人群中进行分析。在第48周，转换组290名参与者中有272名（93.8%）维持病毒载量低于50拷贝/mL，而无转换组139名参与者中有121名（87.1%）（差异6.7%，95% CI 0.4-13.7; p=0.025）。简化方案的统计学优效性主要是由于无转换组中因非病毒学原因停止治疗的受试者比例高于转换组;两组中病毒学失败均罕见（290例中的2例[1%] vs 139例中的2例[1%]）。我们在两组中均未检测到任何治疗后出现的耐药。两组中导致停药的不良事件都很少见（293例中有6例[2%] vs 140例中有4例[3%]）。转换为简化方案与血清肌酐浓度较基线小幅、非进行性升高相关。恶心在转换组中比在无转换组中更常见，但是在转换组中腹泻和腹胀的比率从第4周至第48周与基线相比降低，而在无转换组中这些症状通常没有变化。对于接受多片利托那韦加强蛋白酶抑制剂方案的病毒学抑制的HIV成年人来说，替诺福韦可能是一种有用的方案简化选择。
Background Patients with HIV on antiretroviral therapy might benefit from regimen simplification to reduce pill burden and dosing frequency. We aimed to assess the safety and efficacy of simplifying the treatment regimen for adults with virologically suppressed HIV infection from a ritonavir-boosted protease inhibitor and emtricitabine plus tenofovir disoproxil fumarate (tenofovir) regimen to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir.Methods STRATEGY-PI is a 96 week, international, multicentre, randomised, open-label, phase 3b trial in which HIV infected adults with a plasma HIV-1 RNA viral load of less than 50 copies per mL for at least 6 months who were taking a ritonavir-boosted protease inhibitor with emtricitabine plus tenofovir were randomly assigned (2:1) either to switch to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir or to continue on their existing regimen. Key eligibility criteria included no history of virological failure, no resistance to emtricitabine and tenofovir, and creatinine clearance of 70 mL/min or higher. Neither participants nor investigators were masked to group allocation. The primary endpoint was the proportion of participants with a viral load of less than 50 copies per mL at week 48, based on a US Food and Drug Administration snapshot algorithm for the modified intention-to-treat population, which excluded major protocol violations (prohibited resistance or not receiving a protease inhibitor at baseline). We prespecified non-inferiority with a 12% margin; if non-inferiority was established, superiority was tested as per a prespecified sequential testing procedure. This trial is registered at ClinicalTrials.gov, number NCT01475838.Findings Between Dec 12, 2011, and Dec 20, 2012, 433 participants were randomly assigned and received at least one dose of study drug. Of these participants, 293 were assigned to switch to the simplified regimen (switch group) and 140 to remain on their existing regimen (no-switch group); after exclusions, 290 and 139 participants, respectively, were analysed in the modified intention-to-treat population. At week 48, 272 (93.8%) of 290 participants in the switch group maintained a viral load of less than 50 copies per mL, compared with 121 (87.1%) of 139 in the no-switch group (difference 6.7%, 95% CI 0.4-13.7; p=0.025). The statistical superiority of the simplified regimen was mainly caused by a higher proportion of participants in the no-switch group than in the switch group discontinuing treatment for non-virological reasons; virological failure was rare in both groups (two [1%] of 290 vs two [1%] of 139). We did not detect any treatment-emergent resistance in either group. Adverse events leading to discontinuation were rare in both groups (six [2%] of 293 vs four [3%] of 140). Switching to the simplified regimen was associated with a small, non-progressive increase from baseline in serum creatinine concentration. Nausea was more common in the switch group than in the no-switch group, but rates of diarrhoea and bloating decreased compared with baseline from week 4 to week 48 in the switch group, whereas there were generally no changes for these symptoms in the no-switch group.Interpretation Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir might be a useful regimen simplification option for virologically supressed adults with HIV taking a multitablet ritonavir-boosted protease inhibitor regimen.