Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Lancet Respir Med. 2015 Mar;3(3):201-9. doi: 10.1016/S2213-2600(15)00036-3. Epub 2015 Feb 26.
Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis.
We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling.
We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment.
Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis.
US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
在结核病治疗的 2 期临床试验中，常以痰培养转化作为早期微生物学终点，这是基于其对治疗结束时结局的预测价值，特别是在耐多药结核病（MDR-TB）患者中。我们旨在评估不同时间点固体培养基上的痰培养转化以及转化时间作为 MDR-TB 患者治疗结束时结局的预后标志物的有效性。
我们分析了两项 MDR-TB 大型队列研究的数据。我们将痰培养转化定义为至少相隔 30 天获得的痰样本中连续两次或两次以上的阴性培养。为了评估 2 个月和 6 个月的转化与成功治疗结局的相关性，我们使用随机效应多变量逻辑回归计算了比值比（OR）和 95%置信区间（CI）。我们使用双变量随机效应广义线性混合模型计算了预测值。
我们评估了 1712 例治疗成功、治疗失败或死亡的患者的数据。在治疗成功的患者中，痰培养转化的中位时间明显短于治疗结局不良的患者（2 个月[IQR 1-3] vs 7 个月[3 至≥24]；对数秩检验 p<0·0001）。此外，与失败或死亡相比，6 个月时的转化状态（调整 OR 14·07[95%CI 10·05-19·71]）与治疗成功显著相关。在 HIV 阴性（调整 OR 4·12[95%CI 2·25-7·54]）或未知 HIV 感染（3·59[1·96-6·58]）的患者中，2 个月时的痰培养转化状态与治疗成功显著相关，但在 HIV 阳性患者中则不相关（0·38[0·12-1·18]）。因此，与 2 个月相比，6 个月时痰培养转化与治疗成功的总体相关性要强得多。2 个月的转化率对预测治疗成功的灵敏度较低（27.3%[95%置信区间 16.6-41.4]），特异性较高（89.8%[82.3-94.4]）。相反，6 个月时的痰培养转化状态具有较高的灵敏度（91.8%[85.9-95.4]），但特异性适中（57.8%[42.5-71.6]）。痰培养转化的最大敏感性和特异性在治疗的第 6 个月至第 10 个月之间达到。
对于未知 HIV 感染的 MDR-TB 患者，痰培养转化的时间、6 个月时的转化状态以及 2 个月时的转化状态可以作为治疗结束时结局的替代标志物，尽管与 6 个月时的转化状态相比，与治疗成功的总体相关性要强得多。在设计新的 MDR-TB 治疗方法的 2 期研究时，研究人员在投入大量资源进行大型、长期、3 期试验之前，应考虑这些结果，即不同时间点的痰培养转化作为治疗疗效的早期预测因子的有效性。
美国国际开发署、美国疾病控制与预防中心、美国国立过敏和传染病研究所内部研究部、韩国疾病控制与预防中心。
