Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data
Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data
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DOI：
10.1371/journal.pmed.1003008
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发表时间：
2020-01-01
期刊：
影响因子：
15.8
通讯作者：
Floyd, Katherine
中科院分区：
文献类型：
--
作者：
Dean, Anna S.;Zignol, Matteo;Floyd, Katherine
背景结核病患者耐药性监测对于抗击全球结核病流行和防止抗菌素耐药性蔓延至关重要。异烟肼和利福平是两种最有效的一线抗结核药物，对其中任何一种药物的耐药性都会增加治疗失败、复发或对其他药物产生耐药性的风险。利福平耐药性的全球流行率有充分的记录，2018年新发结核病患者中有3.4% （95% CI 2.5%-4.4%）和以前治疗过的结核病患者中有18% （95% CI 7.6%-31%）出现耐药性，而全球和区域层面的异烟肼耐药性流行率尚不清楚。2018年，世界卫生组织（世卫组织）为耐异烟肼、利福平敏感结核病（Hr-TB）患者推荐了一种修改后的6个月治疗方案，其中包括利福平、吡嗪酰胺、乙胺丁醇和左氧氟沙星。我们估计了结核病患者中Hr-TB的全球患病率，并调查了相关的表型和基因型耐药模式。方法和发现回顾了2003-2017年期间向世卫组织报告的常规连续监测或具有全国代表性的结核病患者定期调查的总体耐药性数据。异烟肼数据来自156个国家或地区，涉及211,753名患者。其中，新发结核病患者的全球Hr-TB患病率为7.4%(95%可信区间为6.5%-8.4%)，以前接受过治疗的结核病患者的全球Hr-TB患病率为11.4%（95%可信区间为9.4%-13.4%）。有关吡嗪酰胺和左氧氟沙星耐药的其他数据来自6个国家（阿塞拜疆、孟加拉国、白俄罗斯、巴基斯坦、菲律宾和南非）。在Hr-TB患者中，除了菲律宾（1.8%,95% CI 0.2-6.4）和白俄罗斯（5.3%,95% CI 0.1-26.0）外，没有对吡嗪酰胺和左氧氟沙星同时耐药的病例。4563例患者异烟肼耐药相关的所有基因组区域的测序数据。在表型检测或测序显示耐药的1174株菌株中，78.6% （95% CI 76.1%-80.9%）在katG基因中存在耐药突变，14.6% （95% CI 12.7%-16.8%）在katG和inhA启动子区域均存在耐药突变。6.8% （95% CI 5.4%-8.4%）的患者仅在inhA启动子中发生突变，可能需要考虑增加异烟肼剂量。本研究的主要局限性是，大多数分析是在国家而不是个体患者水平上进行的，并且实验室检测的质量可能因国家而异。结论在本研究中，全球结核病患者中Hr-TB患病率高于利福平耐药患病率。目前由利福平检测驱动的诊断算法可能会遗漏许多Hr-TB患者，这突出表明需要新的快速分子技术来确保获得适当的治疗和护理。结核病患者对吡嗪酰胺和氟喹诺酮类药物的耐药率较低，这为推荐的改良治疗方案提供了进一步的理由。
BackgroundThe surveillance of drug resistance among tuberculosis (TB) patients is central to combatting the global TB epidemic and preventing the spread of antimicrobial resistance. Isoniazid and rifampicin are two of the most powerful first-line anti-TB medicines, and resistance to either of them increases the risk of treatment failure, relapse, or acquisition of resistance to other drugs. The global prevalence of rifampicin resistance is well documented, occurring in 3.4% (95% CI 2.5%-4.4%) of new TB patients and 18% (95% CI 7.6%-31%) of previously treated TB patients in 2018, whereas the prevalence of isoniazid resistance at global and regional levels is less understood. In 2018, the World Health Organization (WHO) recommended a modified 6-month treatment regimen for people with isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), which includes rifampicin, pyrazinamide, ethambutol, and levofloxacin. We estimated the global prevalence of Hr-TB among TB patients and investigated associated phenotypic and genotypic drug resistance patterns.Methods and findingsAggregated drug resistance data reported to WHO from either routine continuous surveillance or nationally representative periodic surveys of TB patients for the period 2003-2017 were reviewed. Isoniazid data were available from 156 countries or territories for 211,753 patients. Among these, the global prevalence of Hr-TB was 7.4% (95% CI 6.5%-8.4%) among new TB patients and 11.4% (95% CI 9.4%-13.4%) among previously treated TB patients. Additional data on pyrazinamide and levofloxacin resistance were available from 6 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2-6.4) and Belarus (5.3%, 95% CI 0.1-26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%-80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%-16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%-8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries.ConclusionsIn this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen.