利福平耐药性Xpert MTB/RIF检测结果假阳性的患病率及驱动因素：卢旺达的一项前瞻性观察研究

Prevalence and drivers of false-positive rifampicin-resistant Xpert MTB/RIF results: a prospective observational study in Rwanda.

作者信息

Ngabonziza Jean Claude Semuto, Decroo Tom, Migambi Patrick, Habimana Yves Mucyo, Van Deun Armand, Meehan Conor J, Torrea Gabriela, Massou Faridath, de Rijk Willem Bram, Ushizimpumu Bertin, Niyigena Esdras Belamo, Ivan Emil, Semahore Jules Mugabo, Mazarati Jean Baptiste, Merle Corinne Simone, Supply Philip, Affolabi Dissou, Rigouts Leen, de Jong Bouke Catherine

机构信息

National Reference Laboratory Division, Department of Biomedical Services, Rwanda Biomedical Centre, Kigali, Rwanda; Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Research Foundation Flanders, Brussels, Belgium.

出版信息

Lancet Microbe. 2020 Jun;1(2):e74-e83. doi: 10.1016/S2666-5247(20)30007-0. Epub 2020 Jun 8.

DOI:10.1016/S2666-5247(20)30007-0

PMID:35544156

Abstract

BACKGROUND

The Xpert MTB/RIF (Xpert) assay is used globally to rapidly diagnose tuberculosis and resistance to rifampicin. We investigated the frequency and predictors of false-positive findings of rifampicin resistance with Xpert.

METHODS

We did a prospective, observational study of individuals who were enrolled in a Rwandan nationwide diagnostic cohort study (DIAMA trial; NCT03303963). We included patients identified to have rifampicin resistance on initial Xpert testing. We did a repeat Xpert assay and used rpoB Sanger and deep sequencing alongside phenotypic drug susceptibility testing (pDST) to ascertain final rifampicin susceptibility status, with any (hetero)resistant result overriding. We used multivariable logistic regression to assess predictors of false rifampicin resistance on initial Xpert testing, adjusted for HIV status, tuberculosis treatment history, initial Xpert semi-quantitative bacillary load, and initial Xpert probe.

FINDINGS

Between May 4, 2017, and April 30, 2019, 175 people were identified with rifampicin resistance at initial Xpert testing, of whom 154 (88%) underwent repeat Xpert assay. 54 (35%) patients were confirmed as rifampicin resistant on repeat testing and 100 (65%) were not confirmed with resistance. After further testing and sequencing, 121 (79%) of 154 patients had a final confirmed status for rifampicin susceptibility. 57 (47%) of 121 patients were confirmed to have a false rifampicin resistance result and 64 (53%) had true rifampicin resistance. A high pretest probability of rifampicin resistance did not decrease the odds of false rifampicin resistance (adjusted odds ratio [aOR] 6·0, 95% CI 1·0-35·0, for new tuberculosis patients vs patients who needed retreatment). Ten (16%) of the 64 patients with true rifampicin resistance did not have confirmed rifampicin resistance on repeat Xpert testing, of whom four had heteroresistance. Of 63 patients with a very low bacillary load on Xpert testing, 54 (86%) were falsely diagnosed with rifampicin-resistant tuberculosis. Having a very low bacillary load on Xpert testing was strongly associated with false rifampicin resistance at the initial Xpert assay (aOR 63·6, 95% CI 9·9-410·4).

INTERPRETATION

The Xpert testing algorithm should include an assessment of bacillary load and retesting in case rifampicin resistance is detected on a paucibacillary sputum sample. Only when rifampicin resistance has been confirmed on repeat testing should multidrug-resistant tuberculosis treatment be started. When rifampicin resistance has not been confirmed on repeat testing, we propose that patients should be given first-line anti-tuberculosis drugs and monitored closely during treatment, including by baseline culture, pDST, and further Xpert testing.

FUNDING

The European & Developing Countries Clinical Trials Partnership 2 programme, and Belgian Directorate General for Development Cooperation.

摘要

背景

Xpert MTB/RIF检测法在全球范围内用于快速诊断结核病及利福平耐药情况。我们调查了Xpert检测利福平耐药假阳性结果的频率及预测因素。

方法

我们对参与卢旺达全国诊断队列研究（DIAMA试验；NCT03303963）的个体进行了一项前瞻性观察性研究。纳入初次Xpert检测确定为利福平耐药的患者。我们进行了重复Xpert检测，并使用rpoB桑格测序和深度测序以及表型药物敏感性检测（pDST）来确定最终的利福平敏感性状态，任何（异）耐药结果优先。我们使用多变量逻辑回归来评估初次Xpert检测时利福平耐药假阳性的预测因素，并根据HIV状态、结核病治疗史、初次Xpert半定量细菌载量和初次Xpert探针进行调整。

结果

在2017年5月4日至2019年4月30日期间，175人在初次Xpert检测时被确定为利福平耐药，其中154人（88%）接受了重复Xpert检测。54人（35%）在重复检测时被确认为利福平耐药，100人（65%）未被确认耐药。经过进一步检测和测序，154例患者中有一121人（79%）最终确定了利福平敏感性状态。121例患者中有57人（47%）被确认为利福平耐药假阳性结果，64人（53%）为真正的利福平耐药。利福平耐药的高预测试验概率并未降低利福平耐药假阳性的几率（新结核病患者与需要再次治疗的患者相比，调整后的优势比[aOR]为6.0，95%置信区间为1.0 - 35.0）。64例真正利福平耐药的患者中有10人（16%）在重复Xpert检测时未被确认利福平耐药，其中4人有异耐药性。在Xpert检测时细菌载量极低的63例患者中，54人（86%）被误诊为利福平耐药结核病。Xpert检测时细菌载量极低与初次Xpert检测时利福平耐药假阳性密切相关（aOR为63.6，95%置信区间为9.9 - 410.4）。