Baloxavir marboxil
Baloxavir marboxil 是一种 cap-依赖型核酸内切酶抑制剂,可抑制流感病毒聚合酶,因此与神经氨酸酶抑制剂具有不同的作用模式。在美国已经获准将其用于治疗 12 岁及以上年龄患者的非复杂性急性流行性感冒,在其他一些国家也已获批准。研究显示,在体外和体内均可抑制甲型禽流感病毒(H7N9)的复制,[175]Taniguchi K, Ando Y, Nobori H, et al. Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep. 2019 Mar 5;9(1):3466.
https://www.nature.com/articles/s41598-019-39683-4
http://www.ncbi.nlm.nih.gov/pubmed/30837531?tool=bestpractice.com
但是尚无关于在感染人类中疗效的数据,也没有关于将 baloxavir marboxil 用于治疗季节性流感住院患者剂量和有效性的数据。不推荐将单独使用 baloxavir marboxil 作为甲型(H7N9)病毒感染患者的一线治疗。在关于将 baloxavir marboxil 用于季节性流感门诊患者早期治疗的临床试验中,9.7%-23.4% 的患者出现 baloxavir marboxil 耐药标志物。[176]Hayden FG, Sugaya N, Hirotsu N, et al; Baloxavir Marboxil Investigators Group. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018 Sep 6;379(10):913-23.
https://www.nejm.org/doi/10.1056/NEJMoa1716197
http://www.ncbi.nlm.nih.gov/pubmed/30184455?tool=bestpractice.com
[177]Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza. J Infect Dis. 2019 Jul 16 [Epub ahead of print].
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz244/5532607
http://www.ncbi.nlm.nih.gov/pubmed/31309975?tool=bestpractice.com
[178]Omoto S, Speranzini V, Hashimoto T, et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. 2018 Jun 25;8(1):9633.
https://www.nature.com/articles/s41598-018-27890-4
http://www.ncbi.nlm.nih.gov/pubmed/29941893?tool=bestpractice.com
[179]Takashita E, Kawakami C, Morita H, et al; Influenza Virus Surveillance Group Of Japan. Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018. Euro Surveill. 2019 Jan;24(3):ES.2019.24.3.1800698.
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2019.24.3.1800698
http://www.ncbi.nlm.nih.gov/pubmed/30670142?tool=bestpractice.com
cap-依赖型核酸内切酶抑制剂联合神经氨酸酶抑制剂(联合或不联合利巴韦林)应仅用于对照性临床研究背景下。
M2 抑制剂
不推荐单独使用 M2 抑制剂(金刚烷胺和金刚乙胺)作为一线治疗策略。来自人的病毒分离物表现出对 M2 抑制剂的固有耐药性。已将 M2 抑制剂与其他抗病毒药物(具有可能的增效作用)联合使用以治疗甲型流感病毒感染,但仅限于在实验环境中使用。M2 抑制剂与神经氨酸酶抑制剂的联合使用应仅限于临床研究环境中(使用或不使用利巴韦林)。
恢复期血浆
对于亚洲谱系 A 型(H7N9) 病毒感染治疗,仅有一项已发表的非控制治疗的病例报告,并且没有任何恢复期血浆的临床试验。2015 年 1 月,一名存在呼吸衰竭且确诊为亚洲谱系 A 型(H7N9) 病毒感染的 45 岁男性患者接受了奥司他韦治疗。将九个月之前从甲型(H7N9) 病毒感染康复的 H7N9 患者处收集的恢复期血浆加入治疗方案中,发现患者体内甲型(H7N9) 病毒排出,并且完全恢复。[180]Wu XX, Gao HN, Wu HB, et al. Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma. Int J Infect Dis. 2015 Dec;41:3-5.
https://www.ijidonline.com/article/S1201-9712(15)00243-X/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/26482389?tool=bestpractice.com
2006 年 6 月,一名感染了高致病性禽流感甲型 (HPAI) (H5N1) 病毒的 31 岁男性患者,注射了来自今年早些时候甲型(H5N1) 疾病康复患者的恢复期血浆。在给予 3 剂恢复期血浆后,该患者呼吸道样本的甲型HPAI (H5N1) 病毒载量下降,32 小时内水平低至检测不到。[181]Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007 Oct 4;357(14):1450-1.
https://www.nejm.org/doi/10.1056/NEJMc070359
http://www.ncbi.nlm.nih.gov/pubmed/17914053?tool=bestpractice.com
另外两名甲型 HPAI (H5N1) 病毒感染患者接受的恢复期血浆来自甲型(H5N1) 感染康复者或甲型(H5N1) 疫苗接种者。[182]Yu H, Gao Z, Feng Z, et al. Clinical characteristics of 26 human cases of highly pathogenic avian influenza A (H5N1) virus infection in China. PLoS One. 2008 Aug 21;3(8):e2985.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002985
http://www.ncbi.nlm.nih.gov/pubmed/18716658?tool=bestpractice.com
已经完成临床试验,评估用甲型(H5N1) 疫苗产生足以用于恢复期血浆治疗的抗体水平的情况。[183]ClinicalTrials.gov. Development of immune globulin treatment for avian flu. Apr 2016 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT00383071
在对 93 例严重甲型流感(H1N1)pdm09 病毒感染患者进行的前瞻性队列研究中,有 23 例患者注射了高抗体滴度恢复期血浆。治疗组的死亡率显著低于未经治疗组(20.0% vs. 54.8%;p = 0.01)。还发现治疗组的呼吸道病毒载量和血清细胞因子减少。[184]Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56.
https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/ciq106
http://www.ncbi.nlm.nih.gov/pubmed/21248066?tool=bestpractice.com
恢复期血浆疗法处于实验阶段,尚未批准临床上用于治疗任何流感病毒引起的疾病。
静脉注射神经氨酸酶抑制剂
目前已经开发了神经氨酸酶抑制剂的肠外制剂,并且可用于特定的临床情况。静脉注射帕拉米韦 (peramivir)[185]Kohno S, Yen MY, Cheong HJ, et al; S-021812 Clinical Study Group. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother. 2011 Nov;55(11):5267-76.
https://aac.asm.org/content/55/11/5267.long
http://www.ncbi.nlm.nih.gov/pubmed/21825298?tool=bestpractice.com
[186]Kohno S, Kida H, Mizuguchi M, et al; S-021812 Clinical Study Group. Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011 Jun;55(6):2803-12.
https://aac.asm.org/content/55/6/2803.long
http://www.ncbi.nlm.nih.gov/pubmed/21464252?tool=bestpractice.com
[187]Lee N, Chan PK, Tam WW, et al. Virological response to peramivir treatment in adults hospitalised for influenza-associated lower respiratory tract infections. Int J Antimicrob Agents. 2016 Aug;48(2):215-9.
http://www.ncbi.nlm.nih.gov/pubmed/27319273?tool=bestpractice.com
已在美国被批准用于 2 岁及以上非复杂性季节性流感患者的早期治疗,在日本、欧洲和韩国也已获得批准。使季节性流感病毒对奥司他韦产生耐药性的常见耐药性突变通常会导致对帕拉米韦产生耐药性;亚洲谱系甲型(H7N9)病毒的奥司他韦耐药性性突变还可能导致对帕拉米韦的耐药性。静脉用扎那米韦已于 2019 年在欧洲被批准用于治疗 6 月龄及以上患者可能致命的复杂性流行性感冒,但在美国尚未获批准。一项关于比较静脉用扎那米韦与口服奥司他韦治疗季节性流感住院患者的研究未能证明其优越性。[188]Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med. 2017 Feb;5(2):135-46.
http://www.ncbi.nlm.nih.gov/pubmed/28094141?tool=bestpractice.com
在 2009-2010年 H1N1 流感大流行期间及后时期,静脉用扎那米韦由生产商在国际上通过同情使用计划向符合特定处方标准的季节性流感患者提供,但在美国不再使用。虽然一些对奥司他韦具有耐药性的甲型流感病毒对扎那米韦仍然敏感,但除奥司他韦和帕拉米韦外,一些突变还可导致对扎那米韦的敏感性降低或产生耐药性。在中国一些 H7N9 感染患者的治疗过程中已出现了甲型(H7N9)病毒对所有神经氨酸酶抑制剂耐药的情况。[37]Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013 Jun 29;381(9885):2273-9.
http://www.ncbi.nlm.nih.gov/pubmed/23726392?tool=bestpractice.com
[52]Kile JC, Ren R, Liu L, et al. Update: increase in human infections with novel Asian lineage avian influenza A(H7N9) viruses during the fifth epidemic - China, October 1, 2016-August 7, 2017. MMWR Morb Mortal Wkly Rep. 2017 Sep 8;66(35):928-32.
https://www.cdc.gov/mmwr/volumes/66/wr/mm6635a2.htm?s_cid=mm6635a2_e
http://www.ncbi.nlm.nih.gov/pubmed/28880856?tool=bestpractice.com
也可能发生多种突变;推荐进行专业的抗病毒药敏性试验。世界卫生组织(World Health Organization,WHO)推荐,静脉用神经氨酸酶抑制剂治疗应按照相关应急使用的规定使用。[142]World Health Organization. WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Feb 2010 [internet publication].
https://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/
拉尼米韦 (Laninamivir)
一种用于对抗季节性流感的全新吸入型神经氨酸酶抑制剂拉尼米韦,在日本获得批准。它在化学结构上类似于扎那米韦,在肺中转换成活性形式,并维持于较高浓度,一次性给药可用于季节性流感的治疗。亚洲谱系 A 型(H7N9) 病毒分离株在体外似乎对拉尼米韦敏感。[99]Watanabe T, Kiso M, Fukuyama S, et al. Characterization of H7N9 influenza A viruses isolated from humans. Nature. 2013 Sep 26;501(7468):551-5.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891892/
http://www.ncbi.nlm.nih.gov/pubmed/23842494?tool=bestpractice.com
对于拉尼米韦对亚洲谱系 A 型(H7N9) 病毒感染的临床疗效所知甚少,目前不推荐用于该病毒感染的治疗。[189]Ikematsu H, Kawai N. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza. Expert Rev Anti Infect Ther. 2011 Oct;9(10):851-7.
http://www.ncbi.nlm.nih.gov/pubmed/21973296?tool=bestpractice.com
法匹拉韦
法匹拉韦 (Favipiravir) 是一种新型口服药物,已在日本被批准用于治疗成人新发或复发的流感病毒感染(仅限于其他抗流感病毒药物无效或效果不佳的病例)。其作用机制是抑制流感病毒 RNA 聚合酶。[190]Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013 Nov;100(2):446-54.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880838/
http://www.ncbi.nlm.nih.gov/pubmed/24084488?tool=bestpractice.com
尽管体外数据已经证明法匹拉韦对亚洲谱系甲型低致病性禽流感(low-pathogenic avian influenza,LPAI)(H7N9)病毒具有抑制作用,但缺乏有关使用法匹拉韦治疗甲型(H7N9)病毒感染或严重季节性流感的有用临床数据。
利巴韦林
虽然在大多数国家或地区未批准将利巴韦林用于流感的治疗,但是在小鼠实验模型上已经证实它可以增加奥司他韦抵御某些甲型(H5N1) 病毒的疗效。[191]Ilyushina NA, Hay A, Yilmaz N, et al. Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother. 2008 Nov;52(11):3889-97.
https://aac.asm.org/content/52/11/3889.long
http://www.ncbi.nlm.nih.gov/pubmed/18725448?tool=bestpractice.com
然而,利巴韦林治疗严重急性呼吸综合征 (SARS) 冠状病毒感染患者的研究发现,大剂量利巴韦林和进行性溶血性贫血之间存在较强关联。[192]Muller MP, Dresser L, Raboud J, et al. Adverse events associated with high-dose ribavirin: evidence from the Toronto outbreak of severe acute respiratory syndrome. Pharmacotherapy. 2007 Apr;27(4):494-503.
http://www.ncbi.nlm.nih.gov/pubmed/17381375?tool=bestpractice.com
世界卫生组织小组的结论是,其疗效或安全性数据不足以推荐其用于流感治疗。[142]World Health Organization. WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Feb 2010 [internet publication].
https://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/
该结论可以扩展到甲型(H7N9) 病毒感染的治疗。利巴韦林、M2 抑制剂和神经氨酸酶抑制剂的联合治疗应仅限于临床试验环境下使用。