South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lancet Infect Dis. 2021 Mar;21(3):354-365. doi: 10.1016/S1473-3099(20)30914-2. Epub 2021 Jan 25.
Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.
Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.
20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).
The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.
Bill and Melinda Gates Foundation, South African Medical Research Council.
针对最高危发生结核的个体进行靶向预防治疗可能会通过中断传播来影响疫情。我们使用混合三分组研究设计，平行测试结核转录组特征（RISK11）的性能和特征指导预防治疗的疗效。
从南非五个地理位置不同的社区招募年龄在 18-59 岁的成年志愿者。从合格的志愿者中抽取无 HIV、最近（<3 年前筛查）或筛查时合并症的全血，通过定量 RT-PCR 检测 RISK11。RISK11 阳性的参与者被随机分为每周一次、直接观察、开放标签异烟肼和利福平治疗 12 周（即 RISK11 阳性和 3HP 阳性）或不治疗（即 RISK11 阳性和 3HP 阴性）。合格的 RISK11 阴性志愿者的一部分被随机分配至不治疗（即 RISK11 阴性和 3HP 阴性）。在基线时对所有参与者进行了现有结核病的诊断鉴别。此后，在未治疗的 RISK11 阳性与 RISK11 阴性组中测试了新发结核病的预测鉴别，在 3HP 治疗与未治疗的 RISK11 阳性组中测试了治疗效果，通过 15 个月的主动监测进行。主要终点是经微生物学确认的肺结核。主要观察指标是 RISK11 阳性与 RISK11 阴性参与者的结核病风险比[RR]，以及治疗效果。该试验在 ClinicalTrials.gov 注册，NCT02735590。
共筛选了 20207 名志愿者，招募了 2923 名参与者，包括 RISK11 阳性随机分配至 3HP（n=375）或无 3HP（n=764）的参与者，以及 1784 名 RISK11 阴性参与者。在 15 个月时，RISK11 阳性（3HP 阴性）参与者中累计结核病发病或发病的概率为 0.066（95%CI 0.049 至 0.084），RISK11 阴性参与者为 0.018（0.011 至 0.025）（RR 3.69，95%CI 2.25-6.05）。在 15 个月时，RISK11 阳性参与者中结核病患病率为 47（4.1%），而 RISK11 阴性参与者为 14（0.78%）（诊断 RR 5.13，95%CI 2.93 至 9.43）。在 15 个月时，RISK11 阳性（3HP 阴性）参与者中结核病发病率为 2.09（95%CI 0.97 至 3.19），而 RISK11 阴性参与者为 0.80（0.30 至 1.30）/100 人年（累积发病率比 2.6，95%CI 1.2 至 5.9）。与 3HP 相关的严重不良事件包括一例因意外异烟肼过量导致的癫痫发作住院和一例死因不明的死亡（可能与治疗相关）。在 15 个月时，在接受 3HP 治疗的 RISK11 阳性参与者中，结核病发病率为 1.94（95%CI 0.35 至 3.50），而在未接受治疗的 RISK11 阳性参与者中为 2.09（95%CI 0.97 至 3.19）（疗效 7.0%，95%CI-145 至 65）。
RISK11 特征区分了有现有结核病或进展为新发结核病的个体与保持健康的个体，但在排除基线疾病后，向 RISK11 阳性个体提供 3HP 并不能降低 15 个月内结核病的进展。
比尔和梅琳达盖茨基金会、南非医学研究理事会。
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