Wallis Robert S, Peppard Thomas, Hermann David
Aurum Institute, Johannesburg, South Africa.
Certara, LP, St. Louis, Missouri, United States of America.
PLoS One. 2015 Apr 29;10(4):e0125403. doi: 10.1371/journal.pone.0125403. eCollection 2015.
New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.
Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.
The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.
Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.
迫切需要能够缩短结核病治疗时间且不增加复发风险的新治疗方案。2013年的一项Meta回归分析，使用1973年至1997年发表的试验数据，涉及7793名患者，确定2个月时的痰培养状况和治疗持续时间是复发的独立预测因素。由此产生的模型预测，如果一种新的4个月治疗方案将第2个月时阳性患者的比例降至1%，那么在每组有680名受试者的试验中，复发率>10%的风险将降至10%。1%的目标远低于预期。
使用最近3项氟喹诺酮替代方案（REMox、OFLOTUB和RIFAQUIN）缩短治疗时间的3期试验中8个治疗组的数据，评估并完善2013年Meta回归模型的准确性。然后使用约翰逊等人2009年报告的缩短治疗时间试验的数据对更新后的模型进行测试。
2013年模型预测的复发患者比例与文献报道的观察比例高度相关（R2 = 0.86）。使用先前提出的10%复发率作为结核病控制项目可能认为可接受的最大比例阈值，原始模型正确地将所有4种6个月治疗方案识别为令人满意，4种4个月治疗方案中的3种识别为不令人满意（敏感性 = 100%，特异性 = 75%，阳性预测值 = 80%，阴性预测值 = 100%）。基于66种治疗方案和11181名患者的完整数据集对回归模型进行修订，其预测结果仅有微小变化。使用约翰逊等人缩短治疗时间试验的数据对修订后的模型进行测试，发现两个治疗组报告的复发率与预测结果一致。
基于第2个月培养状况和治疗方案持续时间的复发Meta回归模型可为未来3期结核病临床试验的设计提供参考。
