From NewYork-Presbyterian Queens, Flushing, NY (S.S.-M.); Orlando Immunology Center, Orlando (E.D.), and Fort Lauderdale (G.J.R.) - both in Florida; Infektionsmedizinisches Centrum Hamburg, Hamburg, Germany (H.-J.S.); Vita-Salute University, San Raffaele Scientific Institute, Milan (A.C.); Prism Health North Texas (G.I.S.) and North Texas Infectious Diseases Consultants (M.B.) - both in Dallas; Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand (K.S.); Ruane Clinical Research Group, Los Angeles (P.J.R.), and Gilead Sciences, Foster City (H.W., N.A.M., H.D.-S., R.H.H., D.M.B., M.S.R., J.M.B.) - both in California; the University of Paris and the Department of Infectious Diseases, St. Louis-Lariboisière Hospitals, Assistance Publique-Hôpitaux de Paris, Paris (J.-M.M.); and AlloVir, Cambridge, MA (D.M.B.).
N Engl J Med. 2022 May 12;386(19):1793-1803. doi: 10.1056/NEJMoa2115542.
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.
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 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.
A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log 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).
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. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).
患有多重耐药人类免疫缺陷病毒 1 型（HIV-1）感染的患者治疗选择有限。Lenacapavir 是一种首创的衣壳抑制剂，在 1b 期研究中显示出了显著的抗病毒活性。
在这项 3 期试验中，我们根据筛选和队列选择就诊时血浆 HIV-1 RNA 水平的变化，将多重耐药 HIV-1 感染的患者分为两组。在队列 1 中，患者首先以 2:1 的比例随机分配，在 14 天内接受口服 Lenacapavir 或安慰剂，同时接受他们失败的治疗；在维持期，从第 15 天开始，Lenacapavir 组的患者每 6 个月接受一次皮下 Lenacapavir，安慰剂组的患者接受口服 Lenacapavir，然后接受皮下 Lenacapavir；两组均接受优化的背景治疗。在队列 2 中，所有患者在第 1 天至第 14 天接受开放标签的口服 Lenacapavir 和优化的背景治疗；然后从第 15 天开始每 6 个月接受一次皮下 Lenacapavir。主要终点是队列 1 中至少有 24 名患者在第 15 天病毒载量下降至少 0.5log10 拷贝/ml；次要关键终点是第 26 周时病毒载量小于 50 拷贝/ml。
共纳入 72 名患者，每组 36 名。在队列 1 中，Lenacapavir 组的 24 名患者中有 21 名（88%），安慰剂组的 12 名患者中有 2 名（17%）在第 15 天病毒载量下降至少 0.5log10 拷贝/ml（绝对差异，71%；95%置信区间，35%至 90%）。在第 26 周时，队列 1 中有 81%的患者和队列 2 中有 83%的患者病毒载量小于 50 拷贝/ml，CD4+计数分别平均增加了 75 和 104 个细胞/立方毫米。未发现与 Lenacapavir 相关的严重不良事件。在两个队列中，在维持期，8 名患者（6 名 M66I 取代）出现了与敏感性降低相关的 Lenacapavir 相关衣壳取代。
在患有多重耐药 HIV-1 感染的患者中，接受 Lenacapavir 治疗的患者病毒载量从基线下降的幅度大于接受安慰剂的患者。（由吉利德科学公司资助；CAPELLA 临床试验.gov 编号，NCT04150068。）
