Whole genome sequencing precision medicine strategy to shorten treatment for rifampicin-resistant tuberculosis (SMARTT): a pragmatic, randomised, single-blind phase 4 trial.

We aimed to evaluate the effectiveness of whole genome sequencing (WGS)-guided treatment in shortening duration of treatment for rifampicin-resistant tuberculosis.

我们的目标是评估全基因组测序（WGS）指导下的治疗在缩短利福平耐药结核病治疗疗程方面的有效性。

Methods

We did a pragmatic, randomised, single-blind phase 4 trial in 13 hospitals and 35 clinics in South Africa.

我们在南非的13家医院和35家诊所进行了一项实用的、随机的、单盲的4期试验。

Adults with pulmonary rifampicin-resistant tuberculosis were randomly assigned (1:1, using adaptive randomisation) to standard of care (WHO all-oral 9-month, seven-drug regimen or 18-month individualised regimen) or a four-drug, 6-month WGS-guided regimen generated by a feature-based artificial intelligence (AI) model.

成年肺部利福平耐药结核病患者被随机分配（1:1，使用自适应随机化）到标准治疗（WHO全口服9个月的七药方案或18个月的个体化方案）或由基于特征的人工智能（AI）模型生成的四药、6个月的WGS指导方案。

Bacteriological effectiveness, defined as difference in time to culture conversion measured as change in mycobacterial load using a non-linear mixed-effects model, was the primary outcome.

细菌学有效性，定义为培养转换时间的差异，通过非线性混合效应模型测量分枝杆菌负荷的变化来衡量，是主要结果。

Due to operational constraints and the inability to perform culture-free WGS, we performed an analysis of clinical effectiveness in a modified intention-to-treat(mITT) population (risk difference for unfavourable treatment outcomes, 10% non-inferiority margin) and safety (serious adverse events).

由于操作限制和无法进行无培养全基因组测序，我们在修改后的意向治疗（mITT）人群中进行了临床有效性的分析（不利治疗结果的风险差异，10%的非劣效性边界）和安全性（严重不良事件）。

This trial is registered with ClinicalTrials.gov, NCT05017324.

该试验已在ClinicalTrials.gov注册，注册号为NCT05017324。

Results

204 participants were randomly assigned between Sept 23, 2021, and Feb 9, 2023 (101 to the standard of care group, 103 to the WGS group), of which 162 culture-positive individuals were included in the mITT analysis (78 in the standard of care group, 84 in the WGS group). mITT participants were mostly male (n=120 [74%]) and living with HIV (n=100 [63%]) and had rifampicin-resistant, multidrug-resistant tuberculosis (n=142 [88%]), pre-extensively drug-resistant tuberculosis (n=15 [9%]), or extensively drug-resistant tuberculosis (n=5 [3%]).

204名参与者在2021年9月23日至2023年2月9日期间随机分配（标准护理组101人，全基因组测序组103人），其中162名培养阳性的个体被纳入改良意向治疗(mITT)分析（标准护理组78人，全基因组测序组84人）。

In the WGS group, 15 different individualised regimens were recommended to 81 participants, and median treatment duration was shortened by 2·6 months.

在全基因组测序（WGS）组中，向81名参与者推荐了15种不同的个性化治疗方案，治疗的中位持续时间缩短了2.6个月。

Bacteriological response was similar in both groups with a mean mycobacterial load half-life of 0·30 weeks (95% CI 0·27 to 0·33) in the WGS group versus 0·31 weeks (95% CI 0·31 to 0·31) in the standard of care group (relative difference 0·97, 95% CI -0·86 to 1·07; p=0·26).

两组的细菌学反应相似，全基因组测序（WGS）组的平均分枝杆菌负荷半衰期为0.30周（95%置信区间0.27至0.33），而标准治疗组为0.31周（95%置信区间0.31至0.31）（相对差异0.97，95%置信区间-0.86至1.07；p=0.26）。

Unfavourable treatment outcomes (bacteriological failure, loss to follow-up, or death) were less frequent in the WGS group (20 [24%] of 82 vs 32 [42%] of 77; adjusted risk difference -18·4 percentage points, 95% CI -35.6 to -1.2); superiority p=0.018), mostly due to reduced loss to follow-up.

在全基因组测序（WGS）组中，不利的治疗结果（细菌学失败、失访或死亡）的发生率较低（82例中有20例[24%]，与标准治疗组的77例中有32例[42%]相比；调整后的风险差异为-18.4个百分点，95%置信区间为-35.6至-1.2；优势p=0.018），主要是由于减少了失访。

The frequency of serious adverse events was similar between groups (23 [27%] of 84 in the WGS group vs 26 [33%] of 78 in the standard of care group; risk difference -6% percentage points, 95% CI -8 to 20; p=0.41).

两组之间严重不良事件的发生频率相似（WGS组84例中有23例[27%]，标准治疗组78例中有26例[33%]；风险差异为-6个百分点，95%置信区间为-8至20；p=0.41）。

interpretation

Using WGS and AI to select regimens with optimal drug features had similar bacteriological and superior clinical efficacy compared with standard of care and was safe.

利用全基因组测序(WGS)和人工智能(AI)选择具有最佳药物特征的治疗方案，其细菌学疗效与标准治疗相似，临床疗效更优，并且是安全的。

Future trials should evaluate the effectiveness of culture-free sequencing-guided treatment on relapse-free cure where the standard regimen for rifampicin-resistant, multidrug-resistant tuberculosis is bedaquiline, pretomanid, linezolid, and moxifloxacin.

未来的试验应评估无培养测序指导治疗在无复发生存治愈中的效果，其中利福平耐药、多药耐药结核病的标准方案为贝达喹啉、普雷托马尼德、利奈唑胺和莫西沙星。

funding

Research Foundation Flanders.

弗兰德斯研究基金会。