Data from: Delays and loss to follow up before treatment of drug-resistant TB following implementation of Xpert MTB/RIF in South Africa: a retrospective cohort study

Background:
South Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for TB diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow up) between the numbers of laboratory confirmed RR-TB patients and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa.
Methods and findings:
A nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from 2011 and 2013, before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 months and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with healthcare staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of percentage treatment initiation and time to treatment were weighted to account for the sampling design.
There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts respectively; 92% were newly diagnosed with RR-TB (new RR-TB, no prior RR-TB diagnoses). Nationally, among 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53-57) and 63% (95% CI 61-65) respectively started treatment within 6 months of their diagnostic specimen being sent (p<0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at six months between the 1,368174 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59-65) and the 943ose diagnosed by other methods (64%, 95% CI 61-67) (p=0.39). The median time to treatment decreased from 44 (IQR 20-69) days in 2011 to 22 (IQR 2-43) days in 2013 (p<0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51-73% by six months) and median time to treatment (range 15-36 days, N=1,450), and only 53% of 1,448 new RR-TB who received treatmented patients were recorded on the national RR-TB register.
This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients.
Conclusions:
In 2013, there was a large treatment gap for RR-TB in South Africa which varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, overall a larger proportion of the total RR-TB burden has received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required.

研究背景：
南非利福平耐药结核病（rifampicin-resistant tuberculosis, RR-TB）负担沉重，2014年确诊患者达18734例。随着用于所有疑似结核病患者结核诊断的Xpert MTB/RIF检测（Xpert MTB/RIF test）的推广，确诊患者数量大幅增长。常规汇总数据显示，实验室确诊的RR-TB患者与报告已启动二线治疗（second-line treatment）的患者之间存在巨大的治疗缺口（即治疗前失访）。本研究旨在评估Xpert MTB/RIF检测在南非全国范围内推广后，对RR-TB患者二线治疗启动延迟情况及治疗前失访情况的影响。

研究方法与结果：
本研究开展了一项全国性回顾性队列研究（retrospective cohort study），以评估实验室确诊RR-TB患者的二线治疗启动情况及治疗延迟时长。研究队列纳入2011年（Xpert推广前）及2013年（Xpert推广后）的患者，南非每个省份按顺序纳入约300例确诊RR-TB患者。排除6个月内曾经实验室确诊RR-TB的患者以及正在接受治疗的患者。通过与国家及地方治疗登记系统的数据关联、病历审查、医护人员访谈以及直接联系患者或其家属，确定患者是否启动治疗。额外的实验室数据被用于追踪病例。针对抽样设计的权重校正后，得到全国范围内的治疗启动率及治疗时长估算值。

2011年及2013年队列分别纳入合格患者2508例和2528例；其中92%为初次确诊RR-TB（新发病例，无既往RR-TB确诊史）。全国层面来看，2011年队列的2340例新发病例及2013年队列的2311例新发病例中，分别有55%（95%置信区间[confidence interval, CI]：53~57）和63%（95%CI：61~65）在送检诊断标本后的6个月内启动了治疗（p<0.001）。但在2013年，经Xpert检测确诊的1368例新发病例（62%，95%CI：59~65）与经其他方法确诊的943例新发病例（64%，95%CI：61~67）在6个月内启动治疗的比例并无显著差异（p=0.39）。治疗中位时长从2011年的44天（四分位距[interquartile range, IQR]：20~69）降至2013年的22天（IQR：2~43）（p<0.001）。2013年，南非9个省份的治疗启动率（6个月内启动比例范围为51%~73%）及治疗中位时长（范围为15~36天，N=1450）均存在显著差异；且在1448例接受治疗的新发病例中，仅有53%的患者信息被录入国家RR-TB登记系统。

本回顾性研究存在局限性：无法获取患者未启动治疗的相关原因信息，尤其是治疗前死亡率数据。其他局限性包括：通过姓名及出生日期检索患者个体数据，可能导致部分患者的治疗启动情况被漏记。

研究结论：
2013年，南非RR-TB治疗缺口依然巨大，且各省间差异显著。尽管Xpert检测的推广缩短了治疗延迟时长，但在2013年并未显著缩小治疗缺口。但得益于Xpert检测提升了病例检出率，总体上有更大比例的RR-TB患者获得了治疗，且治疗延迟情况有所改善。尽管如此，仍亟需制定相关策略，进一步提升所有确诊RR-TB患者与治疗服务的衔接效率。