贝达喹啉治疗耐药结核病的研究进展
2017-04-04周为静
周为静,陈 玲
·前沿进展·
贝达喹啉治疗耐药结核病的研究进展
周为静,陈 玲
耐药结核病是全球结核病控制规划面临的主要挑战,需要采用二线抗结核药物治疗,但治疗效果并不十分理想,故亟须研究和开发新型抗结核药物。贝达喹啉(bedaquiline)是过去40多年中美国食品药品监督管理局(FDA)批准用于治疗耐药结核病的第一种药物,该药能有效提高耐药结核病的临床疗效及缩短治疗时间。本文综述了贝达喹啉治疗耐药结核病的作用机制、临床试验、不良反应和药物-药物相互作用及耐药机制的研究进展,以提高临床对贝达喹啉的认识。
耐药结核病;贝达喹啉;综述
最新《全球结核病报告》指出,2015年全球范围内新发结核病人数为1 000万,耐药结核病人数为58万,目前仅有52%的耐多药结核病(MDR-TB)和28%的广泛耐药结核病(XDR-TB)患者得到成功救治[1]。我国每年新发耐药结核病患者约7万例,新发耐药结核病患者约占当年新发结核病患者的5.6%,其中仅30%的患者得到救治。耐药结核病的治疗困难,治疗时间较长(24~27个月),需联合使用多种二线抗结核药物,且疗效欠佳、不良反应较多、价格昂贵。一项有关XDR-TB的Meta分析结果显示,XDR-TB患者使用二线抗结核药物治疗成功率约为44%,病死率为14%~27%[2]。因此,开发新型抗结核药物对缩短治疗时间、改善患者治疗依从性、降低复发风险、降低病死率和控制耐药结核病疫情非常重要。
近年来,10余种新型抗结核药物处于临床和临床前期研究阶段,这些药物与一线、二线抗结核药物具有协同作用但无交叉耐药,其生物活性强、t1/2长、致突变率低,有助于缩短治疗时间等[3],其中最引人注意的是已被批准上市的贝达喹啉(bedaquiline)。贝达喹啉是过去40多年来美国食品药品监督管理局(FDA)批准用于治疗耐药结核病的第一种药物,是对目前抗结核药物的一个补充,对印度、中国等结核病流行国家意义重大。2016年12月,中国国家食品药品监督管理总局批准将富马酸贝达喹啉片作为抗结核药物,用于治疗成年(≥18岁)MDR-TB患者,其有望改善MDR-TB患者的治疗效果,降低我国结核病疾病负担。本文通过检索国内外相关文献,旨在综述贝达喹啉治疗耐药结核病的作用机制、临床试验、不良反应和药物-药物相互作用及耐药机制的最新研究进展,以提高对贝达喹啉的认识、促进临床合理用药。
1 作用机制
贝达喹啉已被证实对革兰阳性菌和革兰阴性菌呈弱活性,其最低抑菌药物浓度(MIC)值>32 mg/L[2,4-5],目前有关其对其他类型微生物(如寄生虫和真菌等)的活性报道较少。贝达喹啉已被证实对各种各样致病性分枝杆菌〔如结核分枝杆菌(Mtb)、麻风分枝杆菌和鸟分枝杆菌〕及非致病性分枝杆菌(如耻垢分枝杆菌)具有选择性活性,MIC值为0.003~0.500 mg/L,其中Mtb和耻垢分枝杆菌对贝达喹啉的敏感性较高,具有0.003 mg/L的等效MIC值;贝达喹啉对敏感和耐药Mtb菌株中的不同细菌亚群显示出不同活性,其对复制活跃的Mtb具有高度抑菌性,在体外其MIC值为0.003~0.120 mg/L[2,4,6-7]。临床研究显示,贝达喹啉与主要抗结核药物联用可改善其灭菌活性,可使70%~100%的感染老鼠痰培养结果转阴[8-9];用药前14 d,贝达喹啉杀菌活性较差,但其可通过增加药物剂量而提高杀菌活性[10-11]。
贝达喹啉的作用靶点是人体内结核杆菌复制和传播所需的F1/F0-ATP合酶的质子泵寡聚亚单位c(AtpE),F1/F0-ATP合酶是氧化磷酸化过程中高度保守和关键性酶,其利用质子动力势的动力学机械驱动ATP产生[12-13];其具有独特的强力和选择性的体外抗分枝杆菌活性谱,但对哺乳动物F1/F0-ATP合酶无抑制作用[14]。RUSTOMJEE等[15]研究结果显示,贝达喹啉治疗初期,Mtb的ATP 浓度尚维持在正常水平,治疗几天后ATP浓度逐渐下降,故贝达喹啉是以时间依赖性杀菌方式发挥抗结核作用。
贝达喹啉是一种阳离子两亲性药物,推测其抗分枝杆菌活性的主要机制可能与F1/F0-ATP合酶介导的抗分枝杆菌作用模式相关,次要机制可能与阳离子两亲性质特别是其对膜离子转运ATP酶的影响有关,这种机制目前尚未进一步探索[16]。
2 临床试验
Ⅰ期临床试验发现,人体内贝达喹啉主要由肝细胞色素P4503A4同工酶代谢,故其与利福霉素类(利福平、利福喷汀及利福布汀)强力细胞色素P4503A4同工酶诱导剂联合使用时血药浓度降低50%,故应避免联合使用[17]。Ⅱ期临床试验发现,接受贝达喹啉/背景方案和安慰剂/背景方案治疗的耐药肺结核患者治愈率分别为62%、44%,治疗时间分别缩短83 d、125 d,提示贝达喹啉/背景方案可提高耐药肺结核的临床疗效、缩短治疗时间[18]。另外,CHURCHYARD等[19]进行的双盲随机对照试验显示,单药贝达喹啉可有效预防MDR-TB、XDR-TB密切接触者发生肺结核,且安全性较高;LEIBERT等[20]研究显示,贝达喹啉能有效缩短活动性结核病及潜伏Mtb感染患者的治疗时间;GUGLIELMETTI等[21]是在知情同意基础上向35例法国MDR-TB患者提供贝达喹啉,其中19例为XDR-TB、14例为早期广泛耐药结核(pre-XDR-TB),平均接受4种抗结核药物治疗,采用贝达喹啉治疗6个月后,28例(占96.6%)患者痰培养阳性转阴,痰培养阳性转阴中值时间为85(8~235)d。SKRAHINA等[22]根据世界卫生组织(WHO)建议制定了包含贝达喹啉在内的治疗方案,结果显示186例(占94%)患者治疗6个月后痰培养阳性转阴,6例(占3%)患者痰培养仍为阳性。
3 不良反应和药物-药物相互作用
贝达喹啉常见不良反应是恶心(占30%)、关节痛(占26%)、头痛(占22%)、出血(占14%)、胸痛(占9%)、厌食症(占7%)和皮疹(占6%)[23],严重不良反应是血清转氨酶水平升高和QT间期延长[23-24]。SKRAHINA等[22]最新研究结果显示,135例(占68%)患者发生代谢和营养障碍(以高尿酸血症最常见),127例(占64%)患者发生肝脏疾病(以肝功能异常最常见),93例(47%)患者发生电解质紊乱(以低镁血症最常见),80例(占41%)患者发生心脏疾病(以异常心电图和心律失常最常见),68例(占35%)患者发生胃肠道疾病(以恶心、呕吐、腹痛最常见),54例(占27%)患者发生血液和淋巴系统疾病(以血小板计数降低最常见)。Ⅱ期临床试验显示,接受贝达喹啉/背景方案治疗的耐药结核病患者病死率约为12.7%,接受安慰剂/背景方案治疗的耐药结核病患者病死率约为2.5%[18,25],分析死亡原因主要为呼吸道感染和非感染性疾病而非贝达喹啉毒性作用;随后有研究显示,与接受安慰剂/背景方案治疗的耐药结核病患者相比,接受贝达喹啉/背景方案治疗的耐药结核病患者病死率增加7%[26]。
贝达喹啉与其他抗结核药物〔包括主要抗结核药物(如利福平、乙胺丁醇和吡嗪酰胺)和二线抗结核药物(如AZD5847、噻唑烷、恶唑烷酮、利福喷汀、利奈唑胺、氯法齐明、BTZ043和PBTZ169)〕联合使用时具有协同作用[27],而与另外一些抗结核药物(如pretonamid)联合使用时具有拮抗作用[28];其可有效治疗感染HIV的肺结核患者[26,29],但许多抗反转录病毒药物(如依法韦仑和洛匹那韦)已被证实与其存在药物相互作用,故需采用替代药物(如奈韦拉平)进行替代治疗[30-31]。
4 耐药机制
目前,临床已确定几种贝达喹啉耐药的分子机制,其中最主要的是两个独立基因突变,第1个基因是atpE,其编码F1/F0-ATP合酶。有研究显示,30%的耐贝达喹啉临床分离株存在atpE突变[32-33],atpE的第63或66位氨基酸突变可使贝达喹啉与ATP合酶C亚单位的结合能力下降[34-35]。与贝达喹啉耐药相关的第2个基因是rv0678,其编码Rv0678蛋白。有研究显示,绝大多数贝达喹啉抗性突变体的rv0678基因均发生突变[32-33,36]。在南非,所有贝达喹啉抗性分离株及一些具有发展为贝达喹啉抗性(MIC增加4倍以上)潜力的分离株的rv0678基因均出现突变[26]。一个来自瑞士的关于贝达喹啉耐药案例也涉及rv0678基因突变[37]。促进贝达喹啉耐药的第2个因素是突变率,取决于临床病变或培养物中细菌群体的药代动力学,贝达喹啉培养物中药物抗性发展速率为1/108 cfu/m,这种耐药率相对较低,与利福平相当[5,36],其细菌密度可通过慢性结核病患者肉芽肿病变获得[38-39]。但atpE和rv0678基因哪个突变率较高仍不能明确,rv0678基因似乎是最有可能性的竞争者[26,37,40]。在目前的抗耐药结核方案中,贝达喹啉的t1/2比其他抗结核药物更长(4.0~5.5个月)[14,30,41],且治疗结束后其长t1/2可能有利于选择抗性群体[42-43]。
5 小结
2012年12月,贝达喹啉被FDA批准用于治疗耐药结核病;2014年3月,贝达喹啉被欧洲药品管理局(EMA)批准用于治疗耐药结核病,贝达喹啉是自1974年利福平之后的第一个具有新型作用机制的抗结核药物,目前正在计划或进行多项临床试验以探索采用贝达喹啉治疗耐药结核病的有效方法。STREAM试验正在评估两种含有贝达喹啉在内的抗结核治疗方案治疗耐药结核病的有效性,目的是开发一种全口服6个月的MDR-TB的治疗方案(NCT02409290)。NIX-TB是一个于2015年初推出的Ⅲ期临床试验(NCT02333799),计划在6~9个月内使用贝达喹啉、PA-824和利奈唑胺治疗XDR-TB[44]。截至2015年10月,全世界有超过1 258例患者采用贝达喹啉治疗获益[45-49]。此外,美国国际开发署已决定在4年内向100多个全球基金资助国家免费提供贝达喹啉[26,46,50]。
贝达喹啉的临床益处是FDA在两个Ⅱb期临床试验后给予加速批准的主要原因,常规药物仅在Ⅲ期临床试验结束后才会批准上市。目前,贝达喹啉尚未在儿童、妊娠期或哺乳期妇女、肺外结核病患者、HIV病毒携带者或其他合并症患者中进行研究,故上述人群在常规使用贝达喹啉前还需进一步研究[51]。
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(本文编辑:谢武英)
ProgressonBedaquilineinTreatingDrug-resistantTuberculosis
ZHOUWei-jing,CHENLing
TheSecondDepartmentofRespiratoryMedicine,theAffiliatedHospitalofZunyiMedicalCollege,Zunyi563000,China
Correspondingauthor:CHENLing,E-mail:Lingjuncd@163.com
Drug-resistant tuberculosis is the major challenge in Global Tuberculosis Control Programme,which needs second-line anti-tuberculosis drugs,but the treatment outcome is not very ideal,so we should develop new anti-tuberculosis drugs.Bedaquiline was the first drug for drug-resistant tuberculosis that approved by FDA in the past 40 years,can effectively improve the clinical effect and shorten the curative time in treating drug-resistant tuberculosis.This paper reviewed the action mechanism,clinic trials,adverse reactions,drug-drug interaction and drug resistance mechanism of bedaquiline in treating drug-resistant tuberculosis,in order to improve the clinical acquaintance of bedaquiline.
Drug-resistant tuberculosis;Bedaquiline;Review
国家自然科学基金面上项目(81360002)
陈玲,E-mail:Lingjuncd@163.com
R 521
A
10.3969/j.issn.1008-5971.2017.08.003
2017-05-23;
2017-08-19)
563000贵州省遵义市,遵义医学院附属医院呼吸二科
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ZHOU W J,CHEN L.Progress on bedaquiline in treating drug-resistant tuberculosis[J].Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease,2017,25(8):11-14.