Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, Germany.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
Lancet Microbe. 2022 Mar;3(3):e203-e214. doi: 10.1016/S2666-5247(21)00239-1. Epub 2022 Jan 24.
The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART).
We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18-65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per μL. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials.gov, NCT02850016. It is closed to new participants, and all follow-up is complete.
Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14-28) in the 3BNC117 plus romidepsin group and 28 days (21-35) in the romidepsin group B (p=0·0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which-increased direct bilirubin-was judged to be related to treatment.
The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART.
amfAR, German Center for Infection Research.
在潜伏期逆转之前使用广泛中和抗 HIV-1 抗体进行治疗，可能有助于清除 HIV-1 感染的 CD4 T 细胞。我们通过在接受抑制性抗逆转录病毒疗法（ART）的 HIV-1 感染者中联合使用广泛中和抗体 3BNC117 和潜伏期逆转剂罗米地辛来检验这一概念。
我们在丹麦、德国和美国的三个大学医院中心进行了一项随机、开放标签、2A 期试验。符合条件的参与者为接受抑制性 ART 治疗至少 18 个月、病毒载量低于 50 拷贝/ml 至少 12 个月、CD4 T 细胞计数大于 500 个/μL 的 18-65 岁病毒学抑制的成年 HIV-1 感染者。参与者被随机分配（1:1）接受 3BNC117 联合罗米地辛或罗米地辛单药治疗，共两个周期。所有参与者在第 0、1 和 2 周（治疗周期 1）及第 8、9 和 10 周（治疗周期 2）接受静脉输注罗米地辛（5mg/m2，持续 120 分钟）。3BNC117 联合罗米地辛组的参与者在每个治疗周期前 2 天接受静脉输注 3BNC117（30mg/kg，持续 60 分钟）。两组均在第 24 周进行分析性治疗中断（ATI）。我们的主要终点是 ATI 期间病毒反弹的时间，所有完成两个治疗周期和 ATI 的参与者均接受评估。我们使用对数秩检验比较两组在 ATI 期间病毒反弹的时间。这项试验在 ClinicalTrials.gov 注册，NCT02850016。该试验已经对新参与者关闭，并且所有随访已经完成。
2017 年 3 月 20 日至 2018 年 8 月 14 日，共纳入 22 名参与者并进行随机分组，其中 11 名参与者接受 3BNC117 联合罗米地辛治疗，11 名参与者接受罗米地辛治疗。19 名参与者完成了两个治疗周期和 ATI：3BNC117 联合罗米地辛组 11 名，罗米地辛组 8 名。3BNC117 联合罗米地辛组 ATI 期间病毒反弹的中位时间为 18 天（IQR 14-28），罗米地辛组为 28 天（21-35）（p=0.0016）。尽管这一差异具有统计学意义，但在两组中，病毒反弹时间的延长均无临床意义。两组所有参与者均报告了不良事件，但 3BNC117 和罗米地辛联合使用总体上是安全的。在 48 周随访期间，罗米地辛组观察到 2 例严重不良事件，其中 1 例（直接胆红素升高）被认为与治疗有关。
3BNC117 和罗米地辛联合使用是安全的，但不能延长接受长期抑制性 ART 的个体在 ATI 期间的病毒反弹时间。我们试验的结果可以作为进一步优化接受抑制性 ART 的 HIV-1 感染者的 HIV-1 治愈策略的基准。
amfAR、德国感染研究中心。
