Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection
Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection
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DOI：
10.1056/nejmoa2115542
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发表时间：
2022-05-12
影响因子：
158.5
通讯作者：
Molina, Jean-Michel
中科院分区：
文献类型：
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作者：
Segal-Maurer, Sorana;DeJesus, Edwin;Molina, Jean-Michel
背景：耐多药的人类免疫缺陷病毒1型(HIV-1)感染患者的治疗选择有限。Lenacapavir是一种一流的衣壳类抑制剂，在1b期研究中显示出显著的抗病毒活性。方法在这项3期试验中，我们根据筛查和队列选择访问期间血浆HIV-1RNA水平的变化，将多药耐药HIV-1感染患者纳入两个队列。在队列1中，患者首先按2：1的比例随机分配，在治疗失败的基础上再接受口服来那帕韦或安慰剂治疗14天；在维持期内，从第15天开始，来纳帕韦组患者每6个月皮下注射一次来纳帕韦，安慰剂组患者先接受口服来纳帕韦，然后再皮下注射来那帕韦；两组都接受了优化的背景治疗。在队列2中，所有患者在第1至14天接受开放标签口服来那帕韦，并进行优化的背景治疗；然后从第15天开始每6个月皮下注射一次来那帕韦。主要终点是队列1中到第15天病毒载量至少减少0.5log(10)拷贝的患者的百分比；关键的次要终点是第26周病毒载量低于每毫升50个拷贝的病毒载量。结果共纳入72例患者，每组36例。在队列1中，服用来那帕韦的24名患者中有21名(88%)和安慰剂组的12名患者中的2名(17%)在第15天前病毒载量每毫升至少减少了0.5log(10)拷贝(绝对差异为71个百分点；95%的可信区间为35-90)。在第26周，队列1中81%的患者和队列2中83%的患者报告的病毒载量低于每毫升50个拷贝，CD4+计数的最小二乘平均增加分别为每立方毫米75和104个细胞。未发现与来那帕韦有关的严重不良事件。在两个队列中，8名患者在维持期发生了与易感性降低相关的与来那帕韦相关的衣壳替换(6名患者有M66I替换)。结论：在多药耐药的HIV-1感染患者中，接受来那帕韦治疗的患者比接受安慰剂治疗的患者的病毒载量较基线有更大的下降。
Background Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. Methods In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log(10) copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. Results A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log(10) copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). Conclusions In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo.