两项预防 HIV-1 感染的中和抗体随机临床试验
Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.
机构信息
From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (L.C., P.B.G., M.J., S.T.K., A.C.C., E.R., Y.H., K.E.M., J. Hural, M.J.M.E., C.B., S.T., N.E., A.K.R., N.K., D.J.D., J.G.K., G.G.), and the Departments of Global Health, Microbiology, and Medicine, University of Washington (J.I.M.), Seattle; the Department of Surgery and Duke Human Vaccine Institute, Duke University Medical Center (D.C.M.), and FHI 360 (N.S., P.A.), Durham, and the Institute for Global Health and Infectious Disease, University of North Carolina, Chapel Hill (M.S.C.) - both in North Carolina; the National Institute for Communicable Diseases of the National Health Laboratory Service (L.M.) and the Antibody Immunity Research Unit, Faculty of Health Sciences (L.M.), and the Perinatal HIV Research Unit, Faculty of Health Sciences (F.L., E.M.L., S.T.), University of the Witwatersrand, Johannesburg, the Desmond Tutu HIV Centre, Department of Medicine and Institute of Infectious Disease and Molecular Medicine (C.O.), and the Division of Medical Virology (C.W.), University of Cape Town, Cape Town, the School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), and the South African Medical Research Council, Tygerberg (G.G.) - all in South Africa; the Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta (S.E.); the University of Zimbabwe College of Health Sciences Clinical Trials Research Centre, Harare, Zimbabwe (N.M.M., P.G.M.); Servicio de Enfermedades Infecciosas y Tropicales, Hospital Nacional Dos de Mayo (P.G.), Asociación Civil Via Libre (R.C.), Asociación Civil Impacta Salud y Educación (J.R.L.), and Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales, Universidad Nacional Mayor de San Marcos (J.S.), Lima, and Association Civil Selva Amazónica, Clinical Research Site, Iquitos (J. Hinojosa) - both in Peru; the Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia (I.F.); the Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York (M.E.S.); Botswana Harvard AIDS Institute, Gaborone, Botswana (J.M.); Brigham and Women's Hospital, Harvard Medical School, Boston (L.R.B.); and the Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville (M.M.G.L.), the Prevention Sciences Program, Division of AIDS (D.N.B.), and the Vaccine Research Center (J.E.L., J.R.M.), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, and Johns Hopkins University School of Medicine, Baltimore (E.P.-M.) - all in Maryland.
出版信息
N Engl J Med. 2021 Mar 18;384(11):1003-1014. doi: 10.1056/NEJMoa2031738.
BACKGROUND
Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear.
METHODS
We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC) of acquired isolates was measured with the TZM-bl assay.
RESULTS
Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates.
CONCLUSIONS
VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).
背景
能否使用广谱中和抗体（bnAb）预防人类免疫缺陷病毒 1 型（HIV-1）感染尚不清楚。
方法
我们在美洲和欧洲的 HVTN 704/HPTN 085 试验中招募了处于感染风险中的顺性别男性和跨性别者，以及在撒哈拉以南非洲的 HVTN 703/HPTN 081 试验中招募了处于感染风险中的女性。参与者被随机分配接受每 8 周一次的 bnAb（VRC01）输注，剂量分别为每公斤 10 毫克或 30 毫克（低剂量组和高剂量组）或安慰剂，共 10 次输注。每 4 周进行一次 HIV-1 检测。采用 TZM-bl 测定法测量获得的分离物的 VRC0180%抑制浓度（IC）。
结果
在每个试验中，每个治疗组的不良事件数量和严重程度相似。在 HVTN 704/HPTN 085 的 2699 名参与者中，低剂量组有 32 人、高剂量组有 28 人、安慰剂组有 38 人感染了 HIV-1。在 HVTN 703/HPTN 081 的 1924 名参与者中，低剂量组有 28 人、高剂量组有 19 人、安慰剂组有 29 人感染了 HIV-1。在 HVTN 704/HPTN 085 中，每 100 人年 HIV-1 感染的发生率在 pooled VRC01 组为 2.35，安慰剂组为 2.98（估计预防效果为 26.6%；95%CI，-11.7 至 51.8；P=0.15），在 HVTN 703/HPTN 081 中，pooled VRC01 组每 100 人年的发生率为 2.49，安慰剂组为 3.10（估计预防效果为 8.8%；95%CI，-45.1 至 42.6；P=0.70）。在对整个试验进行的预先指定分析中，每 100 人年感染 VRC01 敏感分离株（IC<1μg/ml）的发生率在 VRC01 接受者中为 0.20，在安慰剂接受者中为 0.86（估计预防效果为 75.4%；95%CI，45.5 至 88.9）。每个 VRC01 剂量和试验的预防效果相似；VRC01 不能预防其他 HIV-1 分离株的感染。
结论
VRC01 预防 HIV-1 总体感染的效果并不优于安慰剂，但对 VRC01 敏感 HIV-1 分离株的分析提供了 bnAb 预防可能有效的证据。（由美国国立过敏和传染病研究所资助；HVTN 704/HPTN 085 和 HVTN 703/HPTN 081 临床试验注册号：NCT02716675 和 NCT02568215。）
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