Background

Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015–19).

Methods

Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.

Findings

Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9–4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3–21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7–10·5) or to both (XDR tuberculosis: 4·8, 2·0–11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3–1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62–195), with 12 of these 16 having pre-XDR or XDR.

Interpretation

Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.

Funding

National Institute for Communicable Diseases of South Africa.

中文翻译：

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评估耐利福平结核病患者对贝达喹啉耐药的流行病学和遗传特征及临床结果：一项横断面和纵向研究

背景

贝达喹啉可改善耐利福平和耐多药 (MDR) 结核病患者的预后；然而，新出现的阻力威胁着这一成功。我们使用来自南非 (2015-19) 的数据进行了横断面和纵向分析，评估了与贝达喹啉耐药相关的流行病学、遗传基础和治疗结果。

方法

开始以贝达喹啉为基础治疗的耐药结核病患者在基线、第 2 个月和第 6 个月提交了监测样本以及人口统计信息。培养阳性基线和基线后分离株具有确定的表型抗性。符合条件的患者年龄在 12 岁或以上，基线培养样本呈阳性，或者如果样本无效或阴性，则在提交贝达喹啉药物敏感性试验的基线样本后 30 天内提供样本。对于纵向研究，第一个监测样本必须在表型上对贝达喹啉敏感才能纳入。对贝达喹啉耐药菌株和贝达喹啉敏感菌株的一部分进行了全基因组测序。国家传染病研究所结核病参考实验室，和国家结核病监测数据库与电子耐药结核病登记表相匹配。我们评估了基线耐药率、突变、传播、累积耐药发生率以及将耐药风险因素与患者预后相关联的优势比 (OR)。

发现

2015 年 1 月 1 日至 2019 年 7 月 31 日期间，8041 名患者提交了监测样本，其中 2023 名纳入横断面分析，695 名纳入纵向分析。基线贝达喹啉耐药率为 3·8%（2023 名患者中的 76 名；95% CI 2·9-4·6），并且与之前接触过贝达喹啉或氯法齐明有关（OR 7·1，95% CI 2·3 –21·9）和利福平耐药或耐多药结核病，对氟喹诺酮类药物或注射药物有额外的耐药性（广泛耐药[XDR]结核病：4·2、1·7-10·5）或两者（ XDR 结核病：4·8、2·0–11·7)。RV0678突变是表型抗性的唯一遗传基础。基线耐药性可归因于 76 名患者中有 4 名 (5·3%) 以前接触过贝达喹啉或氯法齐明，6 名 (7·9%) 患者是原发性传播。基线贝达喹啉耐药的患者成功治疗结果的几率较低（0·5，0·3-1）。695 名患者中有 16 名（2·3%）在治疗期间出现耐药性，中位时间为 90 天（IQR 62-195），这 16 名患者中有 12 名出现 XDR 前或 XDR。

解释

贝达喹啉耐药与较差的治疗结果相关。对贝达喹啉耐药性的快速评估，特别是当患者之前曾接触过贝达喹啉或氯法齐明时，应优先考虑在基线时或如果患者在治疗 2 个月后培养仍呈阳性。通过使用新的联合疗法、当前的治疗优化和患者支持来预防耐药性是必不可少的。

资金

南非国家传染病研究所。