Departments of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
BMC Infect Dis. 2021 Feb 17;21(1):183. doi: 10.1186/s12879-021-05870-w.
Multidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification.
TB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total).
Rapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs.
ClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.
耐多药结核病（MDR-TB）的治疗效果不佳，需要更有效和创新的治疗方案。新的高效 MDR-TB 治疗方案已取得较高的治疗成功率。然而，那些没有药物敏感性测试（DST）的方案也可能导致耐药性的出现。DST 指导下的精准治疗可能会根据个体情况优化患者的治疗效果，并最大限度地减少耐药性的扩增。
TB-TRUST 是一项 III 期、多中心、开放性、随机对照临床试验，旨在比较世界卫生组织（WHO）短程方案和改良超短程方案治疗氟喹诺酮类和二线注射类药物敏感耐利福平结核病的治疗成功率。对照组采用含注射剂的 WHO 短程方案，疗程为 36-44 周，取决于痰涂片转阴时间。实验组采用改良超短程方案，根据分子 DST 指导，通过全基因组测序（WGS）对吡嗪酰胺进行药敏检测，以优化左氧氟沙星、利奈唑胺、环丝氨酸和吡嗪酰胺治疗方案，使吡嗪酰胺敏感患者的疗程为 24-32 周，而吡嗪酰胺耐药患者的疗程为 36-44 周，用左氧氟沙星、利奈唑胺、环丝氨酸和氯法齐明治疗。主要终点为治疗开始后 84 周无复发的治疗成功率。次要终点包括痰培养转阴时间和不良事件的发生情况。假设单侧检验 α 水平为 0.025，效能为 80%，对照组和实验组（80%对 82%）治疗成功率相差小于 10%，失访率为 5%，则每组显示非劣效性的参与者人数计算为 177 人（总共 354 人）。
快速分子检测可区分适合氟喹诺酮短程方案的患者，WGS 检测结果可将吡嗪酰胺敏感患者的治疗时间缩短至 6 个月。可以预见，不仅是新开发的药物，而且是经过 DST 确认敏感的传统强效药物，都是确保抗 MDR-TB 药物效果的关键因素。作为一种 DST 指导的精准治疗，TB-TRUST 有望优化更多无法负担昂贵新药的患者的治疗效果，并通过合理使用抗结核药物，最大限度地减少甚至避免耐药性的扩增。
ClinicalTrials.gov，NCT03867136。于 2019 年 3 月 7 日注册。
