Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.
Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.
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DOI：
10.1056/nejmoa1608243
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发表时间：
2016-11-24
期刊：
影响因子：
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通讯作者：
Chun TW
中科院分区：
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作者：
Bar KJ;Sneller MC;Harrison LJ;Justement JS;Overton ET;Petrone ME;Salantes DB;Seamon CA;Scheinfeld B;Kwan RW;Learn GH;Proschan MA;Kreider EF;Blazkova J;Bardsley M;Refsland EW;Messer M;Clarridge KE;Tustin NB;Madden PJ;Oden K;O'Dell SJ;Jarocki B;Shiakolas AR;Tressler RL;Doria-Rose NA;Bailer RT;Ledgerwood JE;Capparelli EV;Lynch RM;Graham BS;Moir S;Koup RA;Mascola JR;Hoxie JA;Fauci AS;Tebas P;Chun TW
针对人类免疫缺陷病毒（HIV）的强效和广泛中和抗体（bNAbs）的发现使被动免疫成为预防和治疗HIV感染的潜在策略。我们试图确定被动给药VRC01（一种靶向HIV cd4结合位点的bNAb）是否可以安全地预防或延迟停止抗逆转录病毒治疗（ART）后的血浆病毒反弹。我们进行了两项开放标签试验（AIDS Clinical trials Group [ACTG] A5340和National Institutes of Health [NIH] 15-I-0140），研究VRC01在中断抗逆转录病毒治疗的HIV感染者中的安全性、副作用、药代动力学特性和抗病毒活性。共有24名参与者被纳入研究，并发生了一起严重的酒精相关不良事件。尽管血浆VRC01浓度大于50 μg / ml，但仍发生病毒反弹。在A5340试验中，反弹的中位时间为4周，在NIH试验中为5.6周。研究参与者在第4周比历史对照组更有可能出现病毒抑制（A5340试验的双侧Fisher精确检验显示38%比13%，P = 0.04； NIH试验的双侧Fisher精确检验显示80%比13%，P<0.001），但在第8周差异不显著。对抗逆转录病毒治疗前以及中断抗逆转录病毒治疗前后的病毒种群分析表明，VRC01对反弹病毒施加压力，导致复发病毒受到限制，并选择先前存在和新出现的抗体中和抗性病毒。与历史对照组相比，VRC01略微延迟了试验参与者的血浆病毒反弹，但在第8周时没有维持病毒抑制。在参加这些试验的少数参与者中，未发现单一bNAb （VRC01）被动免疫的安全性问题。（由国家过敏和传染病研究所和其他机构资助；ACTG A5340和NIH 15-I-0140 ClinicalTrials.gov编号，NCT02463227和NCT02471326。）
The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P = 0.04 by a two-sided Fisher’s exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher’s exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization–resistant virus. VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326.)