BACKGROUND Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/μL in SOC, 246/μL in EC, and 241/μL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION Retrospectively registered: ClinicalTrials.gov (NCT02538952).

中文翻译：

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结核病筛查和保留干预措施对博茨瓦纳早期抗逆转录病毒治疗死亡率的影响：一项楔入式整群随机试验。

背景技术未诊断的结核病（TB）仍然是HIV相关死亡率的最常见原因。Xpert MTB / RIF（Xpert）正在全球推广，以提高结核病诊断能力。但是，以前的Xpert影响试验报告说，医疗系统的弱点削弱了这种改进的诊断工具的影响。在博茨瓦纳的Xpert阶段性推广期间，我们评估了一揽子干预措施的影响，该措施包括（1）为加强结核病病例发现（ICF）提供额外支持，（2）对缺少临床任命以支持保留的患者进行主动追踪，以及（3）Xpert替代痰涂片镜检，可降低早期（6个月）抗逆转录病毒疗法（ART）的死亡率。方法在22个诊所中，年龄大于12岁的ART参加者符合以下三个阶段的要求：回顾性护理标准（SOC），前瞻性增强护理（EC），和预期的EC加Xpert（EC + X）阶段。EC和EC + X阶段作为逐步楔入式试验进行。EC阶段的参与者收到了SOC以及干预措施的组成部分1（增强的ICF）和2（主动跟踪），EC + X阶段的参与者得到了SOC以及干预措施的所有三个组成部分。主要和次要目标是分别比较SOC和EC + X以及EC和EC + X阶段之间的全因6个月ART死亡率。我们使用适合研究设计的调整后分析来控制个体水平因素和设施内部相关性的基线差异。结果我们招募了14963名合格患者：SOC 8980，EC 1768和EC + X期4215。接受ART治疗的中位年龄为35岁，女性为64％。SOC中的CD4细胞计数中位数低于后续阶段（SOC为184 /μL，EC为246 /μL，EC + X为241 /μL）。截至ART的6个月，SOC死亡461位（5.3％），EC死亡54位（3.2％），EC + X死亡121位（3.0％）。与SOC相比，EC + X期的6个月死亡率更低（调整后的危险比为0.77； 95％的置信区间为0.61-0.97，p = 0.029）。与EC参与者相比，EC + X参与者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留能力。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。EC + X中为241 /μL）。截至ART的6个月，SOC死亡461位（5.3％），EC死亡54位（3.2％），EC + X死亡121位（3.0％）。与SOC相比，EC + X期的6个月死亡率更低（调整后的危险比为0.77； 95％的置信区间为0.61-0.97，p = 0.029）。与EC参与者相比，EC + X参与者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留能力。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。EC + X中为241 /μL）。截至ART的6个月，SOC死亡461位（5.3％），EC死亡54位（3.2％），EC + X死亡121位（3.0％）。与SOC相比，EC + X期的6个月死亡率更低（调整后的危险比为0.77； 95％的置信区间为0.61-0.97，p = 0.029）。与EC参与者相比，EC + X参与者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留率。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。0％的EC + X参与者已死亡。与SOC相比，EC + X期的6个月死亡率更低（调整后的危险比为0.77； 95％的置信区间为0.61-0.97，p = 0.029）。与EC参与者相比，EC + X参与者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留能力。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。0％的EC + X参与者已死亡。与SOC相比，EC + X期的6个月死亡率更低（调整后的危险比为0.77； 95％的置信区间为0.61-0.97，p = 0.029）。与EC参与者相比，EC + X参与者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留能力。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。EC + X入组者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留率。与其他试验相似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。EC + X入组者的6个月死亡率相似。结论加强ICF和保留的干预与较低的早期ART死亡率相关。这一新证据突显了在许多类似环境中需要加强ICF和保留能力。与其他试验类似，未观察到用Xpert替代痰涂片镜检所带来的额外死亡率。试验注册回顾性注册：ClinicalTrials.gov（NCT02538952）。