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qinxilin 发表于 2017-7-3 08:41

药物敏感结核病治疗方案比较

《WHO药物敏感结核病治疗和患者关怀指南(2017更新版)》要点解读         2017-06-30 结核帮
《WHO药物敏感结核病治疗和患者关怀指南(2017更新版)》要点解读
常蕴青  陈国玺  唐神结
_______________
作者单位:030053 山西省太原市第四人民医院(常蕴青);武汉市肺科医院(陈国玺);首都医科大学附属北京胸科医院  北京市结核病胸部肿瘤研究所(唐神结)
通信作者:唐神结, Email:[email]tangsj1106@sina.com[/email]
摘自:来源:结核病与肺部健康杂志,2017年第2期
[url]https://mp.weixin.qq.com/s?__biz=MzAxMzEzOTU1Mg==&mid=2651022035&idx=1&sn=4510018f1655e0d736816432a994fff6&chksm=8050e9dcb72760ca8b0f32d1e93d8d9a5f8cee054db38790799242b98d0d8b9d89d629d658ef&mpshare=1&scene=22&srcid=0630XSu5bY27bpcILGbsFPvL#rd[/url]
2016年7月,WHO召集了多学科的结核病专家,组成指南编写组(guidelines development group, GDG),对药物敏感结核病的治疗策略进行更新,推出了《WHO药物敏感结核病治疗和患者关怀指南(2017更新版)》[1](简称“《2017指南》”),较之于WHO 2009年的第四版《结核病治疗指南》[2]有了一些修订与更新,笔者仅就其有关药物敏感结核病治疗部分进行要点解读。
一、关于4个月短程治疗方案与6个月标准治疗方案的应用建议
对于药物敏感肺结核的治疗,含氟喹诺酮类药物的4个月短程治疗方案与6个月标准治疗方案(2H-R-Z-E/4H-R)的疗效对比,《2017指南》推荐如下[1]:
尽管短程化疗是全球战略的理想目标,但《2017指南》不建议应用含氟喹诺酮类药物的4个月短程治疗方案,建议应用以利福平为基础的6个月标准治疗方案(2H-R-Z-E/4H-R)(强烈建议,证据质量等级中等)。已经进行过临床试验研究的含氟喹诺酮类药物的4个月短程治疗方案包括:4Mfx-H-R-Z,4Mfx-R-Z-E,2Mfx-R-Z-E/2(Mfx+RFP)2,2Mfx-R-Z-E/4(Mfx+RFP)1,2Gfx-H-R-Z/2Gfx-H-R,2(Gfx-H-R-Z)3/2(Gfx-H-R)3,2(Mfx-H-R-Z)3/2(Mfx-H-R)3。研究结果显示,含氟喹诺酮类药物的4个月短程治疗方案与6个月标准治疗方案相比,在治疗后18个月随访时复发率显著升高,即使在治疗2个月时痰菌阴转率略有升高,但差异无统计学意义[3-6]。此外,两种治疗方案在降低药物不良反应、全因死亡率与结核相关死亡率方面均差异无统计学意义[3-6]。尤其是4Mfx-H-R-Z或4Mfx-R-Z-E方案与6个月标准治疗方案相比,其有益的结果显著降低,即复发率显著升高[3]。同样,2Gfx-H-R-Z/2Gfx-H-R[4]或2Mfx-R-Z-E/2(Mfx+RFP)2[5]方案与6个月标准治疗方案相比,并无显著的优势出现,即复发率明显升高[4-5]。最后,2Gfx-H-R-Z/2Gfx-H-R或2Mfx-H-R-Z/2Mfx-H-R方案由于复发率增高,研究不得不提前终止[6]。此外,由于在药物敏感结核病治疗中应用了氟喹诺酮类药物,加之其高的复发率可能会导致氟喹诺酮类药物的耐药性增加,从而在耐药结核病治疗方案中失去一个重要的药物。鉴于此,GDG认为,尽管疗程缩短了2个月,但其不良反应和死亡率并没有降低,而且复发率增高,因此,仍然推荐使用6个月方案治疗药物敏感肺结核。
二、建议应用固定剂量复合剂
对于药物敏感结核病的治疗,固定剂量复合剂与单独药物制剂的疗效对比,《2017指南》推荐如下[1]:
对于药物敏感结核病的治疗,《2017指南》建议应用固定剂量复合剂优于单独药物制剂的应用(一定条件下建议,证据质量等级低)。GDG提出的证据是基于两篇系统性综述和系统性评价[7-8]。研究表明,固定剂量复合剂在治疗失败、死亡、患者依从性及不良事件方面与单独的药物制剂相当,在治疗2个月时,固定剂量复合剂的痰菌阴转率略高,然而,抗结核药物治疗结束时,痰菌阴转率无明显差异[7-8]。固定剂量复合剂的患者满意率更高,结核复发及获得性耐药方面固定剂量复合剂略高于单独药物制剂,但差异无统计学意义。鉴于以上结果,尤其是患者满意度高,GDG认为,应优先使用固定剂量复合剂。
三、关于间歇用药与每日用药的选择
间歇用药(每周3次)与每日用药(无论是在强化期,还是在巩固期)的有效性评估,《2017指南》推荐如下[1]:
对于所有药物敏感肺结核的治疗,无论在抗结核药物治疗的强化期阶段,还是巩固期阶段,《2017指南》不建议每周3次用药,建议每日用药(一定条件下建议,证据质量等级低)。研究表明,每周3次用药与每日用药相比,无论药物敏感是否明确,每周3次用药在治疗失败、结核复发、获得性耐药方面均有更高的风险[3-4,9-13]。因此,在抗结核药物治疗强化阶段,不应该使用每周3次用药。同样,在抗结核药物治疗的巩固阶段,每周3次用药在治疗失败、结核复发方面仍有更高的比率,但在获得性耐药方面差异无统计学意义。本研究还表明,在治疗的巩固阶段,每周2次用药与每周3次用药在治疗失败、结核复发、获得性耐药方面有更高的比率。因此,在抗结核药物治疗的任何阶段,不应该使用每周2次用药。
四、并发HIV感染药物敏感结核病患者的治疗
对于并发HIV药物敏感结核病的治疗,其抗逆转录病毒治疗(ART)起始
治疗时间的制定,《2017指南》推荐如下[1]:
    1.必须进行ART:应对所有并发HIV的结核病患者进行ART,不管其CD4细胞的计数值多少(强烈建议,证据质量等级高)。
2.进行ART的时机:应首先进行抗结核药物治疗,然后在起始抗结核药物治疗8周内尽快启动ART(强烈建议,证据质量高)。对免疫抑制严重的HIV感染患者(如CD4计数低于50 个/mm3)应在起初抗结核药物治疗2周内开始进行ART。
对于并发HIV感染结核病患者的治疗,早期进行ART在降低发病率和致死率方面至关重要。来自8个临床试验的高质量证据表明,抗结核药物治疗8周内开始进行ART与抗结核药物治疗疗程结束后开始进行ART相比,前者的总死亡率下降[10,14-20]。在CD4计数低于50 个/mm3患者的亚分析中,死亡率的降低有统计学意义[15,17,21-22];来自4个临床试验的高质量证据也表明,起初抗结核药物治疗2周内开始进行ART,患者的死亡率下降[10,15-17]。
五、并发HIV感染患者的抗结核药物治疗方案选择
对于并发HIV感染的药物敏感肺结核病患者,超过8个月的抗结核药物治疗方案与6个月的标准治疗方案(2H-R-Z-E/4H-R)疗效相比,《2017指南》推荐如下[1]:
对于并发HIV感染的药物敏感肺结核病患者,《2017指南》认为6个月的标准治疗方案优于超过8个月的抗结核药物治疗方案(一定条件下建议,证据质量等级极低)。
所有感染HIV的患者,特别是那些同时并发结核病的患者,都应该接受ART。并发HIV感染患者接受ART后期待出现更为有利的结果,因此,并发HIV感染的药物敏感肺结核患者的治疗应该给予含利福平的6个月抗结核药物治疗方案。具体参见WHO的Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, second edition [9]和WHO policy on collaborative TB/HIV activities. Guidelines for national programmes and other stakeholders 2012 [23]。
六、关于糖皮质类固醇在肺外结核病治疗中的应用,指南推荐如下[1]:
1.结核性脑膜炎患者:对于结核性脑膜炎患者,《2017指南》建议开始就应该使用糖皮质类固醇进行辅助治疗,药物包括地塞米松或泼尼松龙,疗程6~8周(强烈建议,证据质量等级中等)。
系统性回顾的随机对照临床试验结果表明,对于结核性脑膜炎患者,在抗结核药物治疗的基础上辅助使用糖皮质类固醇治疗显示出较低的死亡率、致残率和结核复发率。此外,辅助糖皮质类固醇治疗患者的不良事件和严重不良事件发生的比率,包括严重肝损伤,均降低[24-28]。
2.结核性心包炎患者:对于结核性心包炎患者,《2017指南》建议可以辅助使用糖皮质类固醇治疗((一定条件下建议,证据质量等级极低)。
系统性回顾的证据结果表明,对于结核性心包炎患者,辅助使用糖皮质类固醇治疗可以使患者在死亡、缩窄性心包炎及治疗依从性等方面获益。然而,HIV感染是使这些结果变得复杂的一个因素[29-36]。
七、复治结核病患者采用Ⅱ类化疗方案进行治疗是否合适
WHO《2017指南》推荐如下[1]:对于复治结核病的治疗,《2017指南》不建议应用Ⅱ类化疗方案(即复治化疗方案),应根据药物敏感性试验(简称“药敏试验”)结果选择治疗方案(良好的实践支持)。系统性回顾表明,在异烟肼和利福平耐药不确定的情况下,对复治结核病经验性应用Ⅱ类化疗方案会导致难以接受的低治疗成功率(中位治疗成功率为68%)。此外,其他随机对照临床试验和队列研究的系统性回顾分析表明,当患者应用Ⅱ类化疗方案时,对异烟肼耐药的患者较对异烟肼敏感的患者其获得性耐药的比率显著升高,这也表明Ⅱ类化疗方案会诱导耐药出现[37-38]。
纵观WHO《2017指南》,强调对于药物敏感肺结核患者的治疗,应选择6个月标准治疗方案;建议应用固定剂量复合剂进行抗结核药物治疗(优于单独药物制剂);强调了无论在抗结核药物治疗的强化期,还是巩固期,每日用药的重要性;提出无论CD4细胞计数值多少,应对所有并发HIV的结核病患者进行ART,而且应在起始抗结核药物治疗8周内尽快启动ART;对于CD4<50 个/mm3的患者,应在起初抗结核药物治疗2周内进行ART;对于并发HIV感染的药物敏感肺结核病患者,《2017指南》推荐6个月的标准抗结核药物治疗方案,以减少不良结果出现;强调了辅助使用糖皮质激素对于结核性脑膜炎和结核性心包炎患者的有益作用;对于复治结核病患者的治疗,强调应根据药敏试验结果选择治疗方案,避免经验性应用Ⅱ类治疗方案。WHO《2017指南》无疑对全球结核病防治工作起着重要的指导和推动作用,值得学习和参考。
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来源:结核病与肺部健康杂志,2017年第2期

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