造血干细胞移植术后如何管理巨细胞病毒?防控端口须前移!

2022-07-27 梅斯医学 梅斯医学

来特莫韦对CMV具有高度活性,且骨髓抑制、肾毒性风险极小,更无交叉耐药的限制。

异基因造血干细胞移植(allo-HSCT)是目前大部分恶性血液肿瘤、部分良性血液疾病及遗传性疾病的唯一可能治愈手段,但这类患者往往免疫功能低下,易发生各类病原学感染。近几年,随着血液肿瘤患者数量和检出率的增加、移植技术的大力发展,以及糖皮质激素与免疫抑制剂的广泛应用等,血液科所面临的感染防治挑战愈发严峻。

巨细胞病毒(CMV)感染是allo-HSCT受者的常见并发症之一,发生率可高达30%-80%[1]。在健康人群中常呈隐匿性感染,但对于免疫低下或抑制人群来说,会导致急慢性感染以及严重并发症。对于allo-HSCT受者而言,CMV血清学阳性是CMV感染最重要的危险因素,而我国allo-HSCT患者移植前的血清学阳性率最高可达92%[2],若不采取预防措施,80%的患者在移植后出现CMV再激活[3]CMV感染的高发生率以及对患者的诸多危害均给临床诊治带来了极大的挑战。

面对CMV感染及其相关疾病的侵袭,如今临床又有何新策略?

CMV感染主动预防或是关键

CMV感染可引发多种直接和间接效应。其中直接效应是通过CMV病毒新发感染或再激活使病毒复制进入活跃期引发的,CMV感染可能会进一步发展为CMV综合征或终末器官病变,增加患者死亡风险,间接效应则是通过影响免疫系统功能而发生,如其它病原体(如细菌、真菌和其它病毒)感染的发生风险增加、移植物抗宿主病(GVHD)发生风险增加、治疗药物毒性暴露等。

CMV病可涉及几乎所有人体器官系统,可引发严重视网膜炎、间质性肺炎、胃肠道出血、肝炎、胰腺炎等病症,甚至发生进行性肺炎、严重低氧、呼吸衰竭、低血压、弥散性血管内凝血(DIC)、重症出血、多器官衰竭等症状,而导致患者死亡。

其实自1980年代起,研究者就不断探索allo-HSCT术后CMV感染预防策略。随着针对CMV感染防治药物的研发技术的进步以及CMV-DNA监测技术的广泛应用,如今临床中已总结出两种主要的CMV感染预防管理策略——预防和抢先治疗。

抢先治疗虽然是控制CMV感染的有效方法,但仍存在诸多不足。如常用的一线药物——更昔洛韦和缬更昔洛韦存在骨髓抑制等严重不良反应[2],而膦甲酸钠效果虽与更昔洛韦接近,但也易引发肾脏不良反应、电解质紊乱等副作用[4]。此外,由于上述药物的作用靶点均为DNA聚合酶,较易发生交叉耐药[2]。除外药物因素外,病毒监测阈值不统一也是目前CMV感染面临的问题。这些均进一步增加了患者的死亡风险和医疗负担[5,6,7],临床亟需安全且高效的CMV感染应对手段。

来特莫韦作为全球首个且目前唯一用于allo-HSCTCMV血清学阳性的成人受者(R+CMV感染和CMV病的预防药物,国家药品监督管理局(NMPA)已于202112月和20225月正式批准来特莫韦片及来特莫韦注射液上市。来特莫韦的到来弥补了移植后预防的空白,或许将打破当前巨细胞病毒管理的困局,让我们能够从理念上化被动为主动,为患者的生命保驾护航。

主动预防时代来临,allo-HSCT移植术后CMV管理开启新格局

吴德沛教授

中华医学会血液学分会主任委员、苏州大学附属第一医院吴德沛教授表示,要守住巨细胞病毒感染的第一道防线,关键还在于非特异性预防。临床试验及多项真实世界研究均显示,来特莫韦能够有效预防allo-HSCT患者的CMV感染,无明显骨髓抑制、肾毒性等不良反应及交叉耐药,有助于降低HSCT过程中的医疗风险,为保障HSCT成功带来有力支持,也期待这一医学创新成果能够在临床实践中惠及更多血液疾病患者。

与传统被动型抗CMV药物相比,主动型CMV预防药物——来特莫韦具有独特的作用机制,通过结合和抑制UL56UL89处的病毒末端酶复合物,作用于病毒复制的晚期,阻止病毒的剪切和包装[3]

来特莫韦的良好的疗效和安全性也得到了临床研究的印证。一项旨在评估来特莫韦用于巨细胞病毒血清阳性移植受者CMV预防的有效性和安全性的关键期、双盲临床试验[8]中,对随机化时未检测到CMV DNA的患者进行评估,将移植后24周内发生具有临床意义CMV感染(CMV病或导致优先治疗的CMV病毒血症)的患者比例设为主要终点。结果显示:至移植后24周,来特莫韦组有临床意义的CMV感染率较安慰剂组显著降低(18.9% vs 44.3%P0.001);在主要有效性人群中,来特莫韦组移植受者移植后24周的全因死亡率低于安慰剂组(10.2% vs 15.9%P0.03);且两组的不良事件发生率和严重程度总体上相似[5]

  

安慰剂组和来特莫韦组累积CMV感染发生率

  

安慰剂组和来特莫韦组累积全因死亡率

意大利真实世界研究也显示,患者在移植手术后立即启动来特莫韦,持续预防100天,CMV再激活和CMV相关疾病发生率分别降低82%83%180天内移植受者再住院率显著降低39.4%[9]。该项研究证实了来特莫韦可有效降低CMV感染及其相关疾病的发生率。

在多项临床试验及真实世界研究中,来特莫韦均可有效预防allo-HSCT受者CMV感染,并改善患者预后,同时无明显骨髓抑制、肾毒性及交叉耐药等不良反应。此外,来特莫韦的两类剂型可为临床提供更多用药选择,更好地满足患者个性化治疗需求。

作为全球首个获批用于CMV血清阳性的allo-HSCT受者CMV感染的预防药物,来特莫韦不仅能为我国allo-HSCT后受者提供有效保护,也将改变CMV的管理格局和治疗理念,对血液移植及公共卫生领域产生深远影响。鉴于其在国际真实世界数据中降低allo-HSCTCMV相关医疗风险、降低CMV相关治疗和管理成本的出色表现,值得让我们共同期待来特莫韦尽早进入医保,以获得更广泛的应用,为临床诊疗提供更多助力。

小结

造血干细胞移植在血液系统疾病中的重要意义不言而喻,而CMV感染及其相关疾病是影响allo-HSCT及患者预后的重要因素之一。来特莫韦的出现为我国CMV的防控管理带来新的机遇,将病毒防控端口前移,为患者提供疗效与安全性双优的创新解决方案。期待在多方努力下,能不断提高来特莫韦的药物可及性,让更多血液疾病患者享受到前沿创新药物,同时推动我国造血干细胞移植水平再上新台阶。

参考文献:

1.Cho SY, et al. Int J Mol Sci,2019,20(11).

2.丁昊炜等造血干细胞移植患者巨细胞病毒感染危险因素和疗效分析[J].北京大学学报. 2003, 35(6) 596-599

3.Kim ES. Letermovir: First Global Approval. Drugs. 2018;78(1):147-152.

4.Avery RK, et al. Transplantation,2016,100(10):e74-e80.

5.Hakki M, et al. Transplant Cell Ther. 2021 Sep;27(9);707-719

6.Britt W J, Prichard M N. Antiviral research, 2018, 159: 153-174.

7.El Haddad L, et al. J Med Virol. 2020 Jan;92(1):86-95.

8.Marty FM, et al. N Engl J Med. 2017;377(25):2433-2444.

9.Malagola M, et al. Front Cell Dev Biol. 2020;8:534268.

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    2023-03-23 cy0324
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    2022-07-29 俅侠
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    2022-07-29 wwzzly