Alternative Language Abstract 1: Chinese Translation of the abstract Multidrug-resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9153 patients. Into Chinese by authors Chen-Yuan CHIANG, Yuhong Liu 耐 多 药 肺 结 核 治 疗 方 案 和 病 人 转 归 :9153 例 病 例 个 案 资 料 的 荟 萃 分 析 耐 多 药 结 核 病 人 个 案 资 料 荟 萃 分 析 协 作 小 组 摘 要 : 背 景 : 耐 多 药 结 核 病 (MDR-TB) 的 治 疗 是 漫 长 有 毒 性 昂 贵 的, 并 且 通 常 效 果 不 佳 我 们 进 行 了 一 项 病 例 个 案 资 料 的 荟 萃 分 析, 评 估 用 于 MDR-TB 治 疗 的 药 物 种 类 药 物 数 量 和 用 药 时 间 对 于 转 归 的 影 响 方 法 : 利 用 最 近 的 三 篇 系 统 综 述 找 寻 关 于 细 菌 学 确 定 的 MDR-TB 病 人 的 治 疗 转 归 的 研 究 报 告 联 络 研 究 的 作 者, 请 求 提 供 关 于 病 人 临 床 特 征 所 给 予 的 治 疗 以 及 转 归 的 个 案 信 息 使 用 随 机 效 应 多 元 回 归 模 型 估 计 病 人 治 疗 成 功 的 调 整 后 比 值 比 结 果 :32 个 观 察 性 研 究 提 供 了 9153 例 MDR-TB 病 人 治 疗 和 转 归 的 足 够 信 息 与 治 疗 失 败 / 复 发 相 比, 治 疗 成 功 与 下 列 药 物 使 用 相 关 : 新 代 喹 诺 酮 类 药 物 ( 调 整 后 比 值 比 (aor):2.5[95% 可 信 区 间 :1.1, 6.0]), 氧 氟 沙 星 (aor:2.5 [1.6, 3.9]), 乙 硫 异 烟 胺 或 丙 硫 异 烟 胺 (aor: 1.7 [1.3, 2.3]), 最 初 强 化 期 使 用 四 种 或 四 种 以 上 可 能 有 效 的 药 物 (aor: 2.3 [1.3, 3.9]), 继 续 期 使 用 三 种 或 三 种 以 上 可 能 有 效 的 药 物 (aor: 2.7 [1.7, 4.1]) 与 治 疗 失 败 / 复 发 或 死 亡 相 比 较, 结 果 相 似, 治 疗 成 功 与 下 列 药 物 的 使 用 相 关 : 新 代 喹 诺 酮 类 药 物 (aor: 2.7 [1.7, 4.3]), 氧 氟 沙 星 (aor: 2.3 [1.3, 3.8]), 乙 硫 异 烟 胺 或 丙 硫 异 烟 胺 (aor: 1.7 [1.4, 2.1]), 最 初 强 化 期 使 用 四 种 或 四 种 以 上 可 能 有 效 的 药 物 (aor: 2.7 [1.9, 3.9]), 继 续 期 使 用 三 种 或 三 种 以 上 可 能 有 效 的 药 物 (aor: 4.5 [3.4, 6.0]) 结 论 : 在 本 次 病 例 个 案 信 息 的 荟 萃 分 析 中, 耐 多 药 结 核 病 治 疗 成 功 率 和 生 存 率 的 改 善 与 使 用 某 些 氟 喹 诺 酮 类 药 物 乙 硫 异 烟 胺 或 丙 硫 异 烟 胺 以 及 应 用 多 种 有 效 药 物 治 疗 相 关 随 机 对 照 试 验 急 需 开 展, 以 优 化 耐 多 药 结 核 的 治 疗 翻 译 : 刘 宇 红 PLoS Medicine 2012; 9(8):e1001300; doi:10.1371/journal.pmed.1001300
Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta- Analysis of 9,153 Patients SD Ahuja, D Ashkin, M Avendano, R Banerjee, M Bauer, JN Bayona, MC Becerra, A Benedetti, M Burgos, R Centis, ED Chan, CY Chiang, H Cox, L D Ambrosio, K DeRiemer, NH Dung, D Enarson, D Falzon, K Flanagan, J Flood, ML Garcia-Garcia, N Gandhi, RM Granich, MG Hollm-Delgado, TH Holtz, MD Iseman, LG Jarlsberg, S Keshavjee, H-R Kim, W-J Koh, J Lancaster, C Lange, WCM de Lange, V Leimane, CC Leung, J Li, D Menzies, GB Migliori, SP Mishustin, CD Mitnick, M Narita, P O Riordan, M Pai, D Palmero, S-k Park, G Pasvol, J Pena, C Perez-Guzman, MID Quelapio, A Poncede-Leon, V Riekstina, J Robert, S Royce, HS Schaaf, KJ Seung, L Shah, TS Shim, SS Shin, Y Shiraishi, J Sifuentes-Osornio, G Sotgiu, MJ Strand, P Tabarsi, TE Tupasi, R van Altena, M Van der Walt, TS. Van der Werf, MH Vargas, P Viiklepp, J Westenhouse, WW Yew, J-J Yim, on behalf of The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB
Study Selection PLoS Medicine 2012; 9(8):e1001300 doi:10.1371/journal.pmed.1001300
Study Objectives Estimate the associations between treatment factors and clinical outcomes of patients with pulmonary MDR TB Assess the impact of: 1. specific drugs 2. number of drugs 3. duration of treatment, on clinical outcomes of patients with pulmonary MDR TB
Methods Study approved beforehand by the Research Ethics Board of Montreal Chest Institute, McGill University Health Centre, and local ethics boards of originally approved studies De-indentified individual patient information on patient characteristics, treatment, outcomes Treatment outcome definitions: Laserson KF, et al. IJTLD 2005; 9:640-645.
Methods Estimated odds of treatment success (treatment cure or completion) versus (i) treatment failure or relapse; (ii) treatment failure, relapse, or default; (iii) treatment failure, relapse, death or default Random effects multivariable logistic regression models to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI)
Clinical characteristics of MDR TB n (%) Mean age +38.7 years Male sex 6,280 (69%) Smear positive 6,012 (66%) Cavitary lesions 4,723 (52%) Extensive disease 6,753 (74%) HIV positive 1,077 (12%) Prior TB therapy 6,683 (73%) Prior therapy with second-line drug 942 (10%)
Treatment for MDR TB n (%) Rifabutin 930 ( 1.4%) Ethambutol 4,722 (52%) Pyrazinamide 6,571 (72%) Ciprofloxacin 986 (11%) Ofloxacin 6,489 (71%) Later generation fluoroquinolones 1,258 (14%) Streptomycin 1,326 (14%) Kanamycin 5,002 (55%) Amikacin 428 ( 5%) Capreomycin 1,757 (19%) Ethionamide 3,873 (42%) Prothionamide 3,709 (41%) PAS 3,196 (33%) One Group 5 drug 2,115 (23%) > 2 Group 5 drugs 594 ( 7%)
Overall Outcomes of Treatment for MDR TB (mutually exclusive) n (%) Treatment success 4,934 (54%) Failed therapy 645 ( 7%) Relapse 87 ( 1%) Default, transfer out, unknown 2,095 (23%) Died during therapy 1,392 (15%)
Summary of association of use of individual drugs with treatment success Ahuja SD, Ashkin D, Avendano M, Banerjee R, et al. (2012) Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients. PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001300
Association of treatment success with duration Ahuja SD, Ashkin D, Avendano M, Banerjee R, et al. (2012) Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients. PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001300
Conclusions Factors associated with treatment success and survival of pulmonary MDR TB patients: Use of later generation quinolones, oflaxacin and ethionamide/prothionamide were associated with treatment success compared to treatment failure, relapse or death Use of > 4 effective drugs (based on DST) during intensive phase Use of > 3 effective drugs (based on DST) during continuation phase Initial treatment phase 7.1-8.5 months Total duration of treatment 18.6 21.5 months
Limitations Retrospective, observational study design Different field studies used different guidelines and case management strategies, depending on the country and clinical practice Availability of second-line drugs varied between studies Specimens were not available for additional analyses, for example, genome sequencing Nevertheless, the study points to the potential of a future, prospective study Collaborations across different sites and countries? Standardized data collection? Multiple specimens per individual patient at different time points during the course of therapy?
Clinical and Program Perspective 4+ step categorical process: Screening/ Testing Diagnosis Treatment Outcome Treatment Success Not A Treatment Success Goal: Guidelines for Good Clinical Practice Who, what, when, everywhere
Biologically, A Continuous Process Treatment Outcome Bacterial burden Time - Days, weeks, months, years, lifetime....
Think Inside the Bug Mycobacterium tuberculosis Biologically, A Continuous Process Infection Bacterial burden Time - Days, weeks, months, years, lifetime.... Pathogen s Goal: Multiply and transmit
Think Inside the Bug Mycobacterium tuberculosis Perspective Regimen A Regimen B Regimen C Time Pathogen s Goal: Multiply, diversify and transmit Bacterial burden Bacterial heterogeneity and diversity drug resistance conferring mutations compensatory mutations rare, novel mutations
Think Inside the Bug Mycobacterium tuberculosis Perspective Diversity window Regimen A Reinfection during therapy Regimen C Time Pathogen s Goal: Multiply, diversify and transmit Bacterial burden Bacterial heterogeneity and diversity drug resistance conferring mutations compensatory mutations; rare, novel mutations reinfections
Opportunities Going Forward Implement collaborative prospective human studies with multiple timepoints for specimen and data collection, per individual patient Incorporate new tools to understand how mycobacterial changes, e.g. mutations and genome analysis, impact treatment outcomes Research in China (31 provinces) can contribute to our knowledge and have a significant impact Expand collaborations for a common goal - to improve patient care and patient outcomes