研究背景

作为严重危害人类健康的重要传染病，结核病（Tuberculosis，TB）已位居单一传染病致死的首位。非活动性肺结核（Pulmonary Tuberculosis，PTB）病灶被广泛认为是发展为活动性TB的高危因素。因现有证据质量低，世界卫生组织尚未将此类人群列为结核病预防性治疗（Tuberculosis Preventive Treatment，TPT）的目标人群。为获得非活动PTB大人群真实数据的结果，在有限的资源内，建立TB优先干预措施，从而推动从社区层面的TB发病率下降。据此，本研究拟依托大规模人群的TB主动发现项目，开展不同类型非活动性PTB发病风险研究及TPT的成本效果评价，为精准干预提供数据参考。

研究方法

依托于2020年至2022年衢州市老年人群活动性TB主动发现项目，即对年龄≥65岁衢州市农村常住人口开展标准化问卷调查和胸部X光片（Chest X-ray，CXR），对疑似活动性TB或活动性TB可疑症状者进行活动性TB诊断。本研究共纳入154,028名参与2020年基线调查的人群。随访2年，追踪CXR显示正常、非活动性PTB、非TB性肺部异常的不同人群活动性TB发病情况，探索不同类型的非活动性PTB的活动性TB发病风险。

依托第一部分非活动性PTB发病数据和文献数据，构建不同干预措施的决策树-马尔可夫模型，评估相对于没有干预或对所有结核潜伏感染（Latent tuberculosis infection，LTBI）老年人群进行TPT干预，非活动性PTB的LTBI老年人群进行TPT的成本效果。并运用单因素分析和概率敏感性分析验证估算的成本效果可靠性。

研究结果

在纳入的154,028名参与者中，共有15,037人（9.76%）的CXR结果显示存在非活动性PTB，包括仅有纤维化病灶（31.08%，4,066人）、钙化病灶（10.77%，1,409人）、胸膜增厚（19.57%，2,561人）、硬结性病灶（30.16%，3,946人）以及至少同时存在两种类型病灶（8.42%，1,102人）。在随访期间，共发现462例病原学确诊活动性TB病例，总人群病原学确诊活动性TB发病密度为190/10万人年（CXR正常：110/10万人年，非活动性PTB：730/10万人年，非PTB肺部异常：350/10万人年）。与CXR正常人群相比，非活动性PTB人群发生活动性TB风险显著增加 [调整后风险比（Adjusted Hazard Ratio，aHR）= 6.00，95%置信区间（Confidence Interval）：4.85-7.43）]。纤维化病灶、钙化灶、胸膜增厚及硬结性病灶均增加了活动性TB的发病风险，aHR范围为 2.94 至 6.55。单独存在非活动性PTB或既往有抗TB治疗史均与活动性TB发病风险独立相关，aHR分别为6.96（95%CI：5.59-8.67）和7.67（95%CI：4.26-13.78），其中无抗TB治疗史的非活动性PTB人群占总的10.27%（23,467/228,416），活动性TB发病人数占总的42.13%（166/394）。此外，非活动性PTB与既往抗TB治疗史之间存在显著的交互效应（aHR = 10.50，95%CI：5.93-18.52）。

20年内每10,000名65岁及以上参与者中，相较于无干预组，具有纤维化病灶的LTBI人群采用6周H2P2（6周每周2次异烟肼-利福喷丁）方案的增量成本效果比（Incremental Cost-Effectiveness Ratio，ICER）为-240,345.71CNY/质量调整生命年（Quality-Adjusted Life Year，QALY），减少55.60名新发TB，预防TB费用24,043.57 CNY/例，采用6H（6个月每日1次异烟肼）方案ICER为-238,517.63 CNY/QALY，减少55.43名新发TB，预防TB费用26,438.71 CNY/例；全部LTBI人群采用6周H2P2方案ICER为-96,551.39 CNY/QALY，减少40.99名新发TB，预防TB费用197,943.56 CNY/例，采用6H获得每QALY均超过支付意愿。单因素敏感性分析显示，纤维化病灶LTBI老年人群的活动性TB进展风险、严重不良事件发生率、治疗完成率及治疗费用是影响结果的主要因素，但不论各因素的影响，其期望值为-81734.76，同时概率敏感性分析表明，纤维化病灶的LTBI老年人群开展6周H2P2方案支付意愿为98.20%，均表明6周H2P2方案是更具成本效果的方案。

研究结论

1）存在非活动性PTB病灶是农村老年人群发生活动性TB的独立危险因素。2）存在非活动性PTB病灶且无规范抗TB治疗史的老年人群占农村常住人口的10%，但40%以上的新发TB患者来自这个人群。3）在农村老年人群中针对存在纤维化病灶的LTBI者开展TPT时，6周H2P2方案相较于6H方案是符合成本效果优势。

Background

Tuberculosis (TB) remains a significant infectious disease that severely threatens human health and is the leading cause of death from a single infectious agent. Inactive pulmonary tuberculosis (PTB) lesions are widely recognized as a high-risk factor for progressing to active TB. However, due to the low quality of existing evidence, the World Health Organization (WHO) has not yet included individuals with inactive TB lesions as a target population for Tuberculosis Preventive Treatment (TPT). Real-world data from a large target population can help to establish prioritized TB interventions within limited resources and drive down TB incidence at the community level. This study leverages a large-scale TB active case-finding project to investigate the risk of active TB development among different types of inactive TB lesions and conducts a cost-effectiveness analysis aiming to provide epidemiological evidence and data-driven insights for developing Chest X-ray (CXR) based TB management guidelines and precise intervention strategies.

Methods

The retrospective study was based on a three-year population-based PTB active case-finding project conducted among elderly aged ≥65 years for rural permanent residents, including standardized questionnaire surveys and CXR screening, and suspected active TB cases and individuals presenting TB-suggestive symptoms subsequently underwent confirmatory diagnostic procedures for active tuberculosis. A total of 154,028 subjects who participated in the 2020 baseline survey were included. During the 2-year follow-up, the incidence of active TB was identified among individuals with normal chest X-rays (CXR), inactive PTB, and non-TB pulmonary abnormalities. The risk of active TB development associated with different types of inactive PTB was also assessed.

Based on the finding of inactive PTB from the first part of the study and literature data, a decision tree-Markov model was constructed to assess the cost-effectiveness of TPT in elderly individuals with both inactive PTB and latent TB infection (LTBI) compared to no intervention or TPT among all elderly LTBI individuals. One-way and probabilistic sensitivity analyses were used to verify the validity of the findings.

Results

Among the 154,028 participants, 15,037 (9.76%) showed inactive PTB on CXR, including with only fibrosis lesions (31.08%, 4,066/13,084), with only calcification lesions (10.77%, 1,409/13,084), with only pleural thickening lesions (19.57%, 2,561/13,084), with only nodules lesions (30.16%, 3,946/13,084) and with at least two types of lesions (8.42%, 1,102/13,084). During a 2-year follow-up survey, 462 microbiologically confirmed active TB cases were identified, with an overall incidence density of 190 per 100,000 person-years (normal CXR: 110 per 100,000 person-years; inactive PTB: 730 per 100,000 person-years; nontubercular pulmonary abnormalities: 350 per 100,000 person-years). Compared to individuals with normal CXR, those with inactive PTB had an independently associated with an increased risk of active disease with an adjusted hazard ratio (aHR) of 6.00 [95% confidence interval (CI): 4.85-7.43]. Fibrosis lesions, calcification lesions, pleural thickening lesions, and nodule lesions were significantly associated with an increased risk of active disease, with aHR ranging from 2.94 to 6.55. inactive PTB alone or history of anti-TB treatment alone were independently associated with the risk of active disease with aHRs of 6.96 (95%CI: 5.59-8.67) and 7.67 (95%CI: 4.26-13.78), respectively. Among them, individuals with inactive PTB without history of anti-TB treatment accounted for 10.27% (23,467/228,416) causing 42.13% (166/394) of the total incidence density. A combined effect between inactive PTB and with history of anti-tuberculosis treatment was found with an aHR of 10.50 (95%CI: 5.93-18.52).

For every 10,000 participants aged ≥65 years during 20 years period, compared with the no-intervention group, the incremental cost-effectiveness ratio (ICER) for the 6-week H2P2 (6-week twice-weekly rifapentine and isoniazid regimen) regimen in LTBI individuals years with fibrosis lesions was -240,345.71 Chinese Yuan (CNY) per Quality-Adjusted Life Year (QALY), preventing 55.60 new TB cases, and protection fee was 24,043.57 CNY per TB case while the ICER for the 6H (6-month daily isoniazid regimen) regimen was -238,517.63 CNY per QALY, preventing 55.43 new TB cases, protection fee was 26,438.71 CNY per TB case; the ICER for the 6-week H2P2 regimen in LTBI individuals was -96,551.39 CNY per QALY, preventing 40.99 new TB cases, protection fee was 197,943.56 CNY per TB case while 6H exceeded the willingness-to-pay threshold per QALY. One-way sensitivity analysis revealed that the risk of active TB progression, severe adverse event rates, treatment completion rates, and treatment costs among elderly with fibrosis lesions were the primary factors influencing the results. However, regardless of these factors, the expected value was -500,070.90 CNY, and probabilistic sensitivity analysis further confirmed that the 6-week H2P2 regimen for elderly LTBI individuals with fibrotic lesions had a 98.20%. All these indicated that the 6-week H2P2 regimen had higher cost-effectiveness under the current economic model. Both indicated the 6-week H2P2 regimen representing a more cost-effective strategy.

Conclusions

The presence of inactive PTB lesions serves as an independent risk factor for developing active TB among the elderly in rural areas. 2) The elderly with inactive PTB lesions and no history of standardized anti-TB treatment account for 10% of the rural permanent population, yet over 40% of new TB cases originate from this group. 3) The 6-week H2P2 regimen represents a more cost-effective strategy than the 6H regimen among elderly LTBI individuals with fibrosis lesions in rural areas.