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干扰素β-1b联合洛匹那韦-利托那韦治疗中东呼吸综合征
Interferon Beta-1b and Lopinavir–Ritonavir for Middle East Respiratory Syndrome


Yaseen M. Arabi ... 呼吸系统疾病 • 2020.10.22
相关阅读
• 洛匹那韦-利托那韦治疗重症COVID-19成人住院患者的试验

摘要


背景

重组干扰素β-1b和洛匹那韦-利托那韦联合治疗可否降低中东呼吸综合征(MERS)住院患者的死亡率尚不明确。

 

方法

我们开展了一项随机、适应性、双盲、安慰剂对照试验,本试验在沙特阿拉伯9个研究中心纳入了患者。我们将实验室检查确诊为MERS的住院患者随机分组,两组分别接受为期14日的重组干扰素β-1b+洛匹那韦-利托那韦联合治疗(干预组)或安慰剂治疗。主要结局是90日全因死亡率,单侧P值阈值为0.025。我们进行了预设的亚组分析和安全性分析。由于COVID-19疫情,数据和安全监察委员会要求进行计划外的期中分析,之后又建议终止患者纳入工作,并报告研究结果。

 

结果

共计95例患者被纳入本试验;43例被分配至干预组,52例被分配至安慰剂组。截至第90日,干预组12例患者(28%)和安慰剂组23例患者(44%)已死亡。考虑到本研究的适应性设计,主要结局的分析结果得出的风险差异为-19个百分点(97.5% CI上限,-3;单侧P=0.024)。在预设的亚组分析中,在症状发生后7日内接受治疗达到了低于安慰剂组的90日死亡率(相对危险度,0.19;95% CI,0.05~0.75),而较晚接受治疗则未能达到这一效果。干预组4例患者(9%)和安慰剂组10例患者(19%)发生了严重不良事件。

 

结论

在实验室检查确诊为MERS的住院患者中,重组干扰素β-1b和洛匹那韦-利托那韦联合治疗使患者达到了低于安慰剂组的死亡率。在症状发生后7日内开始接受治疗的情况下,疗效最为明显(由阿卜杜拉国王国际医学研究中心[King Abdullah International Medical Research Center]资助,MIRACLE在ClinicalTrials.gov注册号为NCT02845843)。





作者信息

Yaseen M. Arabi, M.D., Ayed Y. Asiri, M.D., Abdullah M. Assiri, M.D., Hanan H. Balkhy, M.D., Ali Al Bshabshe, M.D., Majed Al Jeraisy, Pharm.D., Yasser Mandourah, M.D., Mohamed H.A. Azzam, M.D., Abdulhadi M. Bin Eshaq, M.D., Sameera Al Johani, M.B., B.S., Shmeylan Al Harbi, Pharm.D., B.C.P.S, Hani A.A. Jokhdar, M.B., Ch.B., Ph.D., Ahmad M. Deeb, R.N., M.S.N., Ziad A. Memish, M.D., Jesna Jose, M.Sc., Sameeh Ghazal, M.D., Sarah Al Faraj, M.D., Ghaleb A. Al Mekhlafi, M.D., Nisreen M. Sherbeeni, M.D., Fatehi E. Elzein, M.D., Fahad Al-Hameed, M.D., Asim Al Saedi, M.D., Naif K. Alharbi, Ph.D., Robert A. Fowler, M.D.C.M., Frederick G. Hayden, M.D., Abdulaziz Al-Dawood, M.D., Mohamed Abdelzaher, M.D., Wail Bajhmom, M.B., B.S., Ph.D., Badriah M. AlMutairi, R.N., Mohamed A. Hussein, M.S.C.S., M.S.P.H., Ph.D., and Adel Alothman, M.D. for the Saudi Critical Care Trials Group†
From the Intensive Care Department (Y.M.A., A.A.-D.) and the Departments of Infection Prevention and Control (H.H.B.), Pathology and Laboratory Medicine (S.A.J.), Pharmaceutical Care (S.A.H.), and Medicine (A.A.), King Abdulaziz Medical City, Ministry of National Guard Health Affairs, the College of Medicine (Y.M.A., S.A.J., A.A.-D., A.A.) and the College of Pharmacy (M.A.J., S.A.H.), King Saud bin Abdulaziz University for Health Sciences, Prince Mohammed bin Abdulaziz Hospital (A.Y.A., Z.A.M., S.G., S.A.F.), Infection Prevention and Control, Preventive Health (A.M.A.), and Deputyship for Public Health (H.A.A.J.), Ministry of Health, Clinical Trials Services (M.A.J., A.M.D., B.M.A.) and the Departments of Biostatistics and Informatics (J.J., M.A.H.) and Infectious Disease Research (N.K.A.), King Abdullah International Medical Research Center, the Military Medical Services, Ministry of Defense (Y.M.), the Department of Intensive Care Services (G.A.A.M.), and the Infectious Diseases Division (N.M.S., F.E.E.), Prince Sultan Military Medical City, and the College of Medicine, Alfaisal University (Z.A.M.), Riyadh, the Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha (A.A.B.), Medical Services (M.H.A.A.) and the Department of Critical Care Medicine (M.A.), King Abdullah Medical Complex, the Health Directorate, Ministry of Health (M.H.A.A.), and the Internal Medicine Department, King Fahad General Hospital, Ministry of Health (W.B.), the Intensive Care Department (F.A.-H.) and the Department of Infection Prevention and Control (A.A.S.), Ministry of National Guard Health Affairs, and the College of Medicine and King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center (F.A.-H., A.A.S.), Jeddah, and the Intensive Care Department, King Khalid Hospital, Najran (A.M.B.E.) — all in Saudi Arabia; the World Health Organization, Geneva (H.H.B.); the Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta (Z.A.M.); the Departments of Critical Care Medicine and Medicine, Sunnybrook Hospital, and the Institute of Health Policy Management and Evaluation, University of Toronto, Toronto (R.A.F.); and the Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.). Address reprint requests to Dr. Arabi at P.O. Box 22490, Riyadh 11426, Saudi Arabia, or at arabi@ngha.med.sa. Adel Alothman, M.D., is deceased. †A full list of the members of the Saudi Critical Care Trials Group is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). 2019 (https://www.who.int/emergencies/mers-cov/en/. opens in new tab).

2. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East respiratory syndrome. N Engl J Med 2017;376:584-594.

3. Arabi YM, Al-Omari A, Mandourah Y, et al. Critically ill patients with the Middle East respiratory syndrome: a multicenter retrospective cohort study. Crit Care Med 2017;45:1683-1695.

4. 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.

5. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis 2013;13:752-761.

6. Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study. Clin Infect Dis 2020;70:1837-1844.

7. Kain T, Lindsay PJ, Adhikari NKJ, Arabi YM, Van Kerkhove MD, Fowler RA. Pharmacologic treatments and supportive care for Middle East respiratory syndrome. Emerg Infect Dis 2020;26:1102-1112.

8. Chu CM, Cheng VCC, Hung IFN, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-256.

9. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013;3:1686-1686.

10. Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013;19:1313-1317.

11. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV) — possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013;17(10):e792-8.

12. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006;3(9):e343-e343.

13. Hart BJ, Dyall J, Postnikova E, et al. Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014;95:571-577.

14. Chan JFW, Chan K-H, Kao RYT, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013;67:606-616.

15. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014;58:4875-4884.

16. Chan JF-W, Yao Y, Yeung M-L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015;212:1904-1913.

17. Arabi YM, Alothman A, Balkhy HH, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 2018;19:81-81.

18. Arabi YM, Asiri AY, Assiri AM, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials 2020;21:8-8.

19. Chang M. Adaptive design theory and implementation using SAS and R. 2nd ed. Boca Raton, FL: Chapman & Hall/CRC Press, 2014:153-180.

20. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995;57:289-300.

21. Katzen J, Kohn R, Houk JL, Ison MG. Early oseltamivir after hospital admission is associated with shortened hospitalization: a 5-year analysis of oseltamivir timing and clinical outcomes. Clin Infect Dis 2019;69:52-58.

22. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2:395-404.

23. Hernu R, Chroboczek T, Madelaine T, et al. Early oseltamivir therapy improves the outcome in critically ill patients with influenza: a propensity analysis. Intensive Care Med 2018;44:257-260.

24. Chan PKS, Lee N, Zaman M, et al. Determinants of antiviral effectiveness in influenza virus A subtype H5N1. J Infect Dis 2012;206:1359-1366.

25. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-1578.

26. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787-1799.

27. Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr 2011;58:385-391.

28. Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on lopinavir-ritonavir. June 29, 2020 (https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdf. opens in new tab).

29. World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. July 4, 2020 (https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19. opens in new tab).

30. Cameron MJ, Kelvin AA, Leon AJ, et al. Lack of innate interferon responses during SARS coronavirus infection in a vaccination and reinfection ferret model. PLoS One 2012;7(9):e45842-e45842.

31. Minakshi R, Padhan K, Rani M, Khan N, Ahmad F, Jameel S. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS One 2009;4(12):e8342-e8342.

32. Siu K-L, Chan C-P, Kok K-H, Woo PC-Y, Jin D-Y. Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain. Cell Mol Immunol 2014;11:141-149.

33. Wathelet MG, Orr M, Frieman MB, Baric RS. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol 2007;81:11620-11633.

34. Lee JY, Bae S, Myoung J. Middle East respiratory syndrome coronavirus-encoded ORF8b strongly antagonizes IFN-β promoter activation: its implication for vaccine design. J Microbiol 2019;57:803-811.

35. Yang Y, Ye F, Zhu N, et al. Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets. Sci Rep 2015;5:17554-17554.

36. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020;181:1036-1045.e9.

37. Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718-724.

38. Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020 September 24 (Epub ahead of print).

39. Bastard P, Rosen LB, Zhang Q, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020 September 24 (Epub ahead of print).

40. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020;395:1695-1704.

41. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV–infected mice. Cell Host Microbe 2016;19:181-193.

42. Channappanavar R, Fehr AR, Zheng J, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 2019;129:3625-3639.

43. Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial. Int Immunopharmacol 2020 August 24 (Epub ahead of print).

44. Davoudi-Monfared E, Rahmani H, Khalili H, et al. A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe Covid-19. Antimicrob Agents Chemother 2020;64(9):e01061-20-e01061-20.

45. Synairgen. Synairgen announces positive results from trial of SNG001 in hospitalised Covid-19 patients. July 20, 2020 (https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen-announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf. opens in new tab).

46. Bellingan G, Maksimow M, Howell DC, et al. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir Med 2014;2:98-107.

47. Ranieri VM, Pettilä V, Karvonen MK, et al. Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial. JAMA 2020;323:725-733.

48. Shankar-Hari M, Calfee CS. Lack of clinical benefit of interferon β-1a among patients with severe acute respiratory distress syndrome: time to overhaul drug trials in ARDS? JAMA 2020 February 17 (Epub ahead of print).

49. Jalkanen J, Pettilä V, Huttunen T, Hollmén M, Jalkanen S. Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. Intensive Care Med 2020 May 19 (Epub ahead of print).

50. Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2021436.

51. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature 2020;585:273-276.

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