试验性治疗
目前没有确切的证据可推荐对疑似或确诊感染患者进行任何病毒特异性治疗。如果使用试验性药物，世界卫生组织 (World Health Organization, WHO) 建议仅在标准研究治疗方案中，以及研究试验的背景下使用这些药物。[89]World Health Organization. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July 2015 [internet publication].
http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf
需要进一步的研究来评估这些药物对 MERS 患者的安全性和有效性。
干扰素-α
研究发现中东呼吸综合征冠状病毒 (MERS-CoV) 对聚乙二醇干扰素-α 的敏感性是严重急性呼吸综合征 (severe acute respiratory syndrome, SARS) 冠状病毒的 50 至 100 倍。[113]Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67:606-616.
http://www.ncbi.nlm.nih.gov/pubmed/24096239?tool=bestpractice.com
干扰素-α-1b 与利巴韦林联用已被证实具有体外抗 MERS-CoV 的活性。[115]Falzarano D, de Wit E, Martellaro C, et al. Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and ribavirin. Sci Rep. 2013;3:1686.
https://www.nature.com/articles/srep01686
http://www.ncbi.nlm.nih.gov/pubmed/23594967?tool=bestpractice.com
与感染控制法相比，使用这种联合疗法的受感染恒河猴病毒载量较低，呼吸窘迫和胸部 X 线检查双侧浸润的发病率降低。[116]Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013;19:1313-1317.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093902/
http://www.ncbi.nlm.nih.gov/pubmed/24013700?tool=bestpractice.com
然而，在 5 例确诊人类病例的队列研究中，该联合疗法未被证明有效。[117]Al-Tawfiq JA, Momattin H, Dib J, et al. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014;20:42-46.
http://www.ijidonline.com/article/S1201-9712(13)00376-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/24406736?tool=bestpractice.com
在一项回顾性研究中研究了聚乙二醇干扰素-α-2a 联合利巴韦林对人类的治疗，并将该疗法与标准支持性治疗进行了比较。研究结果显示，该联合疗法在治疗14 天时，显著提高了患者的存活率；但在 28 天时存活率未达到统计学意义。[25]Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14:1090-1095.
http://www.ncbi.nlm.nih.gov/pubmed/25278221?tool=bestpractice.com
采用本联合疗法治疗有各种潜在疾病患者的研究呈现出不同的结果。[85]Shalhoub S, Al-Zahrani A, Simhairi R, et al. Successful recovery of MERS CoV pneumonia in a patient with acquired immunodeficiency syndrome: a case report. J Clin Virol. 2015;62:69-71.
http://www.ncbi.nlm.nih.gov/pubmed/25542475?tool=bestpractice.com
[118]Khalid M, Al Rabiah F, Khan B, et al. Ribavirin and interferon (IFN)-alpha-2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus (MERS-CoV): a preliminary report of two cases. Antivir Ther. 2015;20:87-91.
http://www.ncbi.nlm.nih.gov/pubmed/24831606?tool=bestpractice.com
[119]Al-Ghamdi M, Mushtaq F, Awn N, et al. MERS CoV infection in two renal transplant recipients: case report. Am J Transplant. 2015;15:1101-1104.
http://www.ncbi.nlm.nih.gov/pubmed/25716741?tool=bestpractice.com
干扰素-β
研究表明，与干扰素-α-2b 和 α-2a 相比，干扰素-β 具有更高的体外抗 MERS-CoV 活性。[112]Hart BJ, Dyall J, Postnikova E, et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol. 2014;95:571-577.
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.061911-0#tab2
http://www.ncbi.nlm.nih.gov/pubmed/24323636?tool=bestpractice.com
一项针对 24 名患者的回顾性研究将干扰素-β 联合利巴韦林的治疗方案与聚乙二醇干扰素-α-2a 联合利巴韦林的方案进行了比较。研究结果发现，两组患者的 28 日存活率并无显著差异。[5]Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha-2a or IFN-beta-1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70:2129-2132.
http://www.ncbi.nlm.nih.gov/pubmed/25900158?tool=bestpractice.com
洛匹那韦
此药物是一种蛋白酶抑制剂，先前已被证实在与利巴韦林联用时可有效治疗 SARS。[120]Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252-256.
http://thorax.bmj.com/content/59/3/252
http://www.ncbi.nlm.nih.gov/pubmed/14985565?tool=bestpractice.com
有研究检测了此药物在体外抗 MERS-CoV 的作用；但结果显示疗效欠佳。[113]Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67:606-616.
http://www.ncbi.nlm.nih.gov/pubmed/24096239?tool=bestpractice.com
在动物研究试验中，与麦考酚酯相比，洛匹那韦的临床结果和存活率更佳。[121]Chan JF, Yao Y, Yeung ML, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212:1904-1913.
http://www.ncbi.nlm.nih.gov/pubmed/26198719?tool=bestpractice.com
一项病例报告显示，其与干扰素和利巴韦林联用时病毒血症可消退。[122]Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents. 2014;44:528-532.
http://www.ncbi.nlm.nih.gov/pubmed/25288266?tool=bestpractice.com
沙特阿拉伯正在进行一项洛匹那韦/利托那韦与干扰素-β 联合用药的安慰剂对照试验。[123]US National Institutes of Health. ClinicalTrials.gov: MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and interferon beta-1b (MIRACLE): a multicenter, placebo-controlled, double-blind randomized trial (trial id NCT02845843). November 2016 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT02845843
环孢素
此药物是一种具有已知抗病毒活性的免疫抑制剂。研究已证明其具有体外抗 MERS-CoV 活性；然而，目前批准的剂量无法达到抗病毒活性所需的血浆峰值水平。[124]de Wilde AH, Raj VS, Oudshoorn D, et al. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment. J Gen Virol. 2013;94:1749-1760.
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.052910-0#tab2
http://www.ncbi.nlm.nih.gov/pubmed/23620378?tool=bestpractice.com
已公布了 2 例因其他医学原因已经接受环孢素治疗，随后死于 MERS 的病例报告。[16]Guery B, Poissy J, el Mansouf L, et al. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet. 2013;381:2265-2272.
http://www.ncbi.nlm.nih.gov/pubmed/23727167?tool=bestpractice.com
[119]Al-Ghamdi M, Mushtaq F, Awn N, et al. MERS CoV infection in two renal transplant recipients: case report. Am J Transplant. 2015;15:1101-1104.
http://www.ncbi.nlm.nih.gov/pubmed/25716741?tool=bestpractice.com
就现有的有限证据而言，是否将环孢素用于治疗还存在疑问。
麦考酚酯
该药物是一种具有已知抗病毒活性的免疫抑制剂。许多体外研究已经证明其具有抗 MERS-CoV 的活性。[112]Hart BJ, Dyall J, Postnikova E, et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol. 2014;95:571-577.
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.061911-0#tab2
http://www.ncbi.nlm.nih.gov/pubmed/24323636?tool=bestpractice.com
[113]Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013;67:606-616.
http://www.ncbi.nlm.nih.gov/pubmed/24096239?tool=bestpractice.com
[125]Pan Q, de Ruiter PE, Metselaar HJ, et al. Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo. Hepatology. 2012;55:1673-1683.
http://www.ncbi.nlm.nih.gov/pubmed/22213147?tool=bestpractice.com
[126]Cheng KW, Cheng SC, Chen WY, et al. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015;115:9-16.
http://www.ncbi.nlm.nih.gov/pubmed/25542975?tool=bestpractice.com
该药物尚未用于动物研究。一例肾移植患者的病例报告显示，该患者服用了麦考酚酯加泼尼松龙，感染 MERS 后得以存活。还有一例病例报告显示，患者在接受麦考酚酯加环孢素和泼尼松龙治疗后未存活。[119]Al-Ghamdi M, Mushtaq F, Awn N, et al. MERS CoV infection in two renal transplant recipients: case report. Am J Transplant. 2015;15:1101-1104.
http://www.ncbi.nlm.nih.gov/pubmed/25716741?tool=bestpractice.com
[127]Mailles A, Blanckaert K, Chaud P, et al. First cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infections in France, investigations and implications for the prevention of human-to-human transmission, France, May 2013. Euro Surveill. 2013;18:20502.
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20502
http://www.ncbi.nlm.nih.gov/pubmed/23787161?tool=bestpractice.com
单克隆抗体
已开发出针对 MERS-CoV 刺突 (S) 蛋白 S1 亚单位上的受体结合域中不同表位的单克隆抗体（例如，Mersmab）。[128]Mou H, Raj VS, van Kuppeveld FJ, et al. The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J Virol. 2013;87:9379-9383.
http://jvi.asm.org/content/87/16/9379.full
http://www.ncbi.nlm.nih.gov/pubmed/23785207?tool=bestpractice.com
[129]Du L, Zhao G, Yang Y, et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J Virol. 2014;88:7045-7053.
http://jvi.asm.org/content/88/12/7045.full
http://www.ncbi.nlm.nih.gov/pubmed/24719424?tool=bestpractice.com
[130]Du L, Kou Z, Ma C, et al. A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PLoS One. 2013;8:e81587.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081587
http://www.ncbi.nlm.nih.gov/pubmed/24324708?tool=bestpractice.com
与宿主细胞表面上的功能性受体二肽基肽酶-4（DPP4，也称为 CD26）相比，这些抗体对受体结合域的亲和力更高（高 10 至 450 倍）。[129]Du L, Zhao G, Yang Y, et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J Virol. 2014;88:7045-7053.
http://jvi.asm.org/content/88/12/7045.full
http://www.ncbi.nlm.nih.gov/pubmed/24719424?tool=bestpractice.com
[131]Ying T, Du L, Ju TW, et al. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol. 2014;88:7796-7805.
http://jvi.asm.org/content/88/14/7796.long
http://www.ncbi.nlm.nih.gov/pubmed/24789777?tool=bestpractice.com
[132]Tang XC, Agnihothram SS, Jiao Y, et al. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci USA. 2014;111:E2018-E2026.
http://www.pnas.org/content/111/19/E2018.full
http://www.ncbi.nlm.nih.gov/pubmed/24778221?tool=bestpractice.com
[133]Jiang L, Wang N, Zuo T, et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med. 2014;6:234ra59.
http://www.ncbi.nlm.nih.gov/pubmed/24778414?tool=bestpractice.com
合成肽
目前已开发出了一种合成肽 (HR2P) 用于阻断 MERS-CoV 病毒 S2 亚单位上的 HR1 域，并已证实其在体外有较强的抗病毒效果。[3]Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522.
http://www.ncbi.nlm.nih.gov/pubmed/25810418?tool=bestpractice.com
[73]Xia S, Liu Q, Wang Q, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res. 2014;194:200-210.
http://www.ncbi.nlm.nih.gov/pubmed/25451066?tool=bestpractice.com
[134]Lu L, Liu Q, Zhu Y, et al. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun. 2014;5:3067.
https://www.nature.com/articles/ncomms4067
http://www.ncbi.nlm.nih.gov/pubmed/24473083?tool=bestpractice.com
已开发出该药物的鼻内制剂 (HR2P-M2)。一项研究表明它对小鼠有效，并且与干扰素-β 联用效果增强。[135]Channappanavar R, Lu L, Xia S, et al. Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J Infect Dis. 2015;212:1894-1903.
http://www.ncbi.nlm.nih.gov/pubmed/26164863?tool=bestpractice.com
恩夫韦地是一种 HIV 融合抑制剂，也是一种 HR2 多肽，因此是另一种潜在的治疗选择。[136]Fung HB, Guo Y. Enfuvirtide: a fusion inhibitor for the treatment of HIV infection. Clin Ther. 2004;26:352-378.
http://www.ncbi.nlm.nih.gov/pubmed/15110129?tool=bestpractice.com
其他药物
使用基于细胞的酶联免疫吸附测定 (enzyme-linked immunosorbent assayELISA) 筛选多种有抗 MERS-CoV 活性的化合物，并且发现 60 种药物表现出活性，包括氯丙嗪、他莫昔芬和氯喹。[3]Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522.
http://www.ncbi.nlm.nih.gov/pubmed/25810418?tool=bestpractice.com