Inducing Durable Immunological Control of HIV-1 Through Administration of Long-acting Broadly Neutralizing Antibodies and Low-dose Anti-PD-1 - a Randomized, Double-blinded, Placebocontrolled Trial (the IDUNN Trial)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 90
- 主要终点
- Time from the day of stopping ART to the day of meeting criteria for loss of immunological control of HIV-1 (defined below)
研究概览
简要总结
Antiretroviral therapy (ART) has significantly extended the life expectancy of people living with HIV-1 (PLWH), but it does not cure the infection. Broadly neutralizing antibodies (bNAbs), such as 3BNC117 and 10-1074, not only neutralize circulating virus but also engage the immune system to enhance HIV-1-specific CD8+ T cell responses and stimulate autologous neutralizing antibody production. In some individuals who discontinue ART, bNAb treatment resulted in long-term post-treatment control. However, a major obstacle to immunotherapeutic strategies in PLWH is the immune dysfunction that persists despite long-term suppressive ART. One contributing factor is the immune checkpoint receptor programmed death-1 (PD-1), which is expressed on T cells and suppresses their function when engaged by its ligands. Blocking PD-1 with monoclonal antibodies (mAbs) can reverse T cell exhaustion, a strategy that has resulted in extraordinary increases in survival and cure in cancer treatment and in ex vivo and animal studies of HIV. These findings support the rationale for incorporating PD-1 inhibition in HIV cure strategies. Low-dose nivolumab, an anti-PD-1 mAb, has been shown to be safe in clinical trials. The hypothesis is that combining a single low-dose of nivolumab with long-acting bNAbs (3BNC117-LS and 10-1074-LS) during an analytical treatment interruption (ATI) will reduce T cell exhaustion and boost HIV-1-specific immune responses, as a novel strategy to induce sustained virological control without ART even after the bNAbs have been cleared from the body.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability and willingness to provide informed consent
- •HBV sAg or HBV DNA as well as HCV Ag or HCV RNA negative or anti-core antibody negative
- •Current CD4 count >500 cells/μL (at screening)
- •Plasma HIV-1 RNA <50 copies/mL by standard assays for at least 15 months (a single measurement >50 but <500 copies/mL during this time period is allowable)
- •On integrase inhibitor (INSTI) or boosted protease inhibitor (PI) based regimen at time of randomization, if previously on non-nucleoside reverse transcriptase inhibitor (NNRTI) has switched at least 4 weeks prior to randomization
- •Females of childbearing potential (i.e., participants who have not been postmenopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy), negative serum or urine pregnancy test monthly
- •Pregnancy prevention (heterosexual contact(s)):
- •o Females must agree to use highly eWective contraceptive methods: Hormonal contraception, intrauterine device, or intrauterine hormone-releasing system from at least 2 weeks before the bNAb infusion and for entire trial period of 60 weeks and 15 months following the bNAb infusion
- •Transmission prevention
- •Participants must agree to use barrier prevention during ART interruption and until plasma HIV-1 RNA levels are resuppressed again following ART re-start
- •Partners of study participants should be willing to receive counselling on the need for PrEP according to national recommendations
排除标准
- •Current, or history of:
- •Clinically significant cardiovascular disease (e.g., cardiac insuWiciency, coronary artery disease, cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, family history of sudden death)
- •Malignancy, excluding non-melanoma skin cancers
- •Solid organ transplant
- •Autoimmune or antibody-mediated diseases (including not limited to type 1 diabetes mellitus, inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insuWiciency, hypothyroidism and/or hyperthyroidism, autoimmune thyroiditis, sarcoidosis, and vitiligo)
- •Known hypersensitivity to the components of 3BNC117-LS, 10-1074-LS or nivolumab or their analogues
- •HIV-1 reservoir predicted resistant to neutralization by 10-1074 using genotypic analysis (as defined in section 11.3.2.9)
- •Known HIV-1 subtype CRF01-AE due to resistance to 10-1074-LS
- •Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to screening
- •Laboratory abnormalities in the parameters listed below:
- •Estimated glomerular filtration rate (eGFR) <60 mL/min
- •AST or ALT >x1.25 upper limit of normal (ULN)
- •Positive Quantiferon test
- •TPO antibodies >35 IU/mL
- •Partial thromboplastin time >1.25 ULN
- •Pregnancy or lactation
- •Any vaccination 2 weeks prior to baseline
- •Any significant acute infection (e.g. influenza, COVID-19) or any other clinically significant illness 2 weeks prior to screening
- •Have received a long-acting ART regimen within the last 12 months (e.g. cabotegravir or lenacaprivir containing regimen)
- •Known resistance to >2 classes of ART
- •Participation in other interventional trial
- •Any other conditions, which in the opinion of the investigator would make the participant unsuitable for inclusion, or could interfere with the participants participating in or completion of the study
研究组 & 干预措施
B: bNAbs/placebo
3BNC117-LS, 10-1074-LS and placebo
干预措施: Placebo (Other)
A: bNAbs/anti-PD-1a
3BNC117-LS, 10-1074-LS and nivolumab
干预措施: 3BNC117-LS (Drug)
A: bNAbs/anti-PD-1a
3BNC117-LS, 10-1074-LS and nivolumab
干预措施: Nivolumab (Drug)
B: bNAbs/placebo
3BNC117-LS, 10-1074-LS and placebo
干预措施: 10-1074-LS (Drug)
A: bNAbs/anti-PD-1a
3BNC117-LS, 10-1074-LS and nivolumab
干预措施: 10-1074-LS (Drug)
B: bNAbs/placebo
3BNC117-LS, 10-1074-LS and placebo
干预措施: 3BNC117-LS (Drug)
结局指标
主要结局
Time from the day of stopping ART to the day of meeting criteria for loss of immunological control of HIV-1 (defined below)
时间窗: 60 weeks
Loss of immunological control of HIV-1 is defined as one or more of the following three criteria: * Six weeks of consecutive plasma HIV-1 RNA \>1,000 copies/mL or confirmed \>100,000 copies/mL * Confirmed (on two consecutive measurements) CD4+ T cell count \<350 cells/mm3 * Participant's request or if the ATI in the opinion of the Sponsor or Investigator poses an unacceptable risk to the participant
次要结局
- The safety and tolerability of the Investigational Medicinal Products (IMPs)(Adverse events will be recorded from signing of the informed consent form and until end of study week 60 or visit 50 following restart of ART, whichever comes first.)
- The frequency of post-interventional immunological control of HIV-1(At week 24, 36, 48 and 60)
- The effect of the IMPs on HIV-1-specific T cells responses before, during and after the ATI(From baseline to weeks 8, 12, 16, 24 and 60 or ART-restart, whichever comes first)
- The effect of the IMPs on the intact HIV-1 reservoir before, during and after the ATI(From baseline to weeks 24 and 60 or ART-restart, whichever comes first)
- The effect of the IMPs on the immune cell phenotype, activation and exhaustion(From baseline to weeks 8, 16, 24 and 60 or ART-restart, whichever comes first)
- The effect of autologous antibodies on post-interventional immunological control of HIV-1(Time from the day of stopping ART to weeks 24 and 60 or day of restarting ART, whichever comes first)
- bNAb sensitivity(Baseline and time of ART re-initiation (visit 30) during the 60 weeks of ATI)
研究者
Ole Schmeltz Søgaard
Professor
Aarhus University Hospital