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TLR9 激动剂和广谱中和抗体对 HIV-1 持续感染的影响：随机 2a 期 TITAN 试验。

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.

机构信息

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.

出版信息

Nat Med. 2023 Oct;29(10):2547-2558. doi: 10.1038/s41591-023-02547-6. Epub 2023 Sep 11.

DOI:10.1038/s41591-023-02547-6
PMID:37696935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10579101/
Abstract

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

摘要

诱导抗逆转录病毒疗法 (ART) 无病毒学控制是实现人类免疫缺陷病毒 1 型 (HIV-1) 治愈的关键步骤。在这项 2a 期、安慰剂对照、双盲试验中，43 名接受 ART 的 HIV-1 感染者（85%为男性）被随机分为 (1) 安慰剂/安慰剂、(2) lefitolimod（TLR9 激动剂）/安慰剂、(3) 安慰剂/广谱中和抗 HIV-1 抗体 (bNAb) 或 (4) lefitolimod/bNAb。ART 中断 (ATI) 于第 3 周开始。lefitolimod 在第 1 至 8 周每周给药 1 次，bNAb 在 ATI 前 1 天和 3 周后各给药 2 次。主要终点是 ATI 后失去病毒学控制的时间。与安慰剂/安慰剂组相比，lefitolimod/安慰剂、安慰剂/bNAb 和 lefitolimod/bNAb 组的病毒学控制丢失时间中位数延迟分别为 0.5 周（P=0.49）、12.5 周（P=0.003）和 9.5 周（P=0.004）。在次要终点中，与非 bNAb 组相比，bNAb 组的病毒倍增时间较慢，并且干预措施总体上是安全的。我们没有观察到 lefitolimod 的额外益处。尽管血浆 bNAb 水平低于治疗水平，但在安慰剂/bNAb 组中有 36%（4/11）在 25 周 ATI 后维持病毒学控制，而安慰剂/安慰剂组中无 0%（0/10）。尽管 lefitolimod 免疫疗法并未导致 ART 无 HIV-1 控制，但 bNAb 可能是未来 HIV-1 治愈策略的重要组成部分。临床试验.gov 标识符：NCT03837756。

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