摘要
背景
目前尚无任何经证实可有效治疗SARS-CoV-2所致重症疾病的方法。
方法
我们在确诊SARS-CoV-2感染（患呼吸系统疾病COVID-19）并且呼吸周围空气时氧饱和度（SaO2）≤94%或者氧分压（PaO2）与吸入氧浓度（FiO2）的比值＜300 mmHg的成人住院患者中开展了一项随机、对照、开放标签的试验。我们以1∶1的比例将患者随机分组，分别接受常规治疗联合14日的每日2次洛匹那韦-利托那韦（分别为400 mg和100 mg）治疗或单独常规治疗。主要终点是至临床状况改善的时间，其定义为从随机分组至7分等级量表评分改善2分或者出院（以先发生的一项为准）的时间。
结果
共计199例实验室确诊SARS-CoV-2感染的患者被随机分组：99例被分配至洛匹那韦-利托那韦组，100例被分配至常规治疗组。在至临床状况改善的时间方面，洛匹那韦-利托那韦治疗与常规治疗无差异（临床改善的风险比，1.24；95%置信区间[CI]，0.90～1.72）。洛匹那韦-利托那韦组和常规治疗组的28日死亡率相似（19.2%vs. 25.0%；差异，－5.8个百分点；95% CI，－17.3～5.7）。两组在各时间点可检出病毒RNA的患者百分比相似。在改良意向治疗分析中，与常规治疗相比，洛匹那韦-利托那韦治疗使至临床状况改善的中位时间提前了1日（风险比，1.39；95% CI，1.00～1.91）。洛匹那韦-利托那韦组的胃肠道不良事件发生率较高，但常规治疗组的严重不良事件发生率较高。13例患者（13.8%）因不良事件提前停止洛匹那韦-利托那韦治疗。
结论
在重症COVID-19成人住院患者中，与常规治疗相比，我们未观察到洛匹那韦-利托那韦治疗有益。未来对重症患者开展的试验可能有助于确认或排除该方案产生益处的可能性（由中国国家重大新药创制科技重大专项等资助，中国临床试验注册号为ChiCTR2000029308）。
作者信息
Bin Cao, M.D., Yeming Wang, M.D., Danning Wen, M.D., Wen Liu, M.S., Jingli Wang, M.D., Guohui Fan, M.S., Lianguo Ruan, M.D., Bin Song, M.D., Yanping Cai, M.D., Ming Wei, M.D., Xingwang Li, M.D., Jiaan Xia, M.D., Nanshan Chen, M.D., Jie Xiang, M.D., Ting Yu, M.D., Tao Bai, M.D., Xuelei Xie, M.D., Li Zhang, M.D., Caihong Li, M.D., Ye Yuan, M.D., Hua Chen, M.D., Huadong Li, M.D., Hanping Huang, M.D., Shengjing Tu, M.D., Fengyun Gong, M.D., Ying Liu, M.S., Yuan Wei, M.D., Chongya Dong, Ph.D., Fei Zhou, M.D., Xiaoying Gu, Ph.D., Jiuyang Xu, M.D., Zhibo Liu, M.D., Yi Zhang, M.D., Hui Li, M.D., Lianhan Shang, M.D., Ke Wang, M.D., Kunxia Li, M.D., Xia Zhou, M.D., Xuan Dong, M.D., Zhaohui Qu, M.D., Sixia Lu, M.D., Xujuan Hu, M.D., Shunan Ruan, M.S., Shanshan Luo, M.D., Jing Wu, M.D., Lu Peng, M.D., Fang Cheng, M.D., Lihong Pan, M.D., Jun Zou, M.D., Chunmin Jia, M.D., Juan Wang, M.D., Xia Liu, M.D., Shuzhen Wang, M.S., Xudong Wu, M.S., Qin Ge, M.S., Jing He, M.S., Haiyan Zhan, M.S., Fang Qiu, M.S., Li Guo, Ph.D., Chaolin Huang, M.D., Thomas Jaki, Ph.D., Frederick G. Hayden, M.D., Peter W. Horby, M.D., Dingyu Zhang, M.D., and Chen Wang, M.D.
From the Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases (B.C., Yeming Wang, G.F., F.Z., X.G., Z.L., Y.Z., Hui Li, L.S., C.W.), and the Institute of Clinical Medical Sciences (G.F., X.G.), China–Japan Friendship Hospital, the Institute of Respiratory Medicine, Chinese Academy of Medical Sciences (B.C., Yeming Wang, F.Z., Z.L., Y.Z., Hui Li, C.W.), the Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (Xingwang Li), Peking University Clinical Research Institute, Peking University First Hospital (C.D.), Tsinghua University School of Medicine (Jiuyang Xu), Beijing University of Chinese Medicine (L.S.), NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences (L.G.), and Peking Union Medical College (L.G., C.W.), Beijing, and Jin Yin-tan Hospital, Wuhan (D.W., W.L., Jingli Wang, L.R., B.S., Y.C., M.W., Jiaan Xia, N.C., Jie Xiang, T.Y., T.B., X.X., L.Z., C.L., Y.Y., H.C., Huadong Li, H.H., S.T., F.G., Y.L., Yuan Wei, K.W., K.L., X.Z., X.D., Z.Q., Sixia Lu, X.H., S.R., Shanshan Luo, Jing Wu, Lu Peng, F.C., Lihong Pan, J.Z., C.J., Juan Wang, Xia Liu, S.W., X.W., Q.G., J.H., H.Z., F.Q., C.H., D.Z.) — all in China; Lancaster University, Lancaster (T.J.), and the University of Oxford, Oxford (P.W.H.) — both in the United Kingdom; and the University of Virginia School of Medicine, Charlottesville (F.G.H.). Address reprint requests to Dr. Cao at caobin_ben@163.com, to Dr. C. Wang at cyh-birm@263.net, or to Dr. D. Zhang at 1813886398@qq.com.
参考文献
1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
2. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-513.
3. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 February 7 (Epub ahead of print).
4. Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl) 2020 February 7 (Epub ahead of print).
5. 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.
6. Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004;31:69-75.
7. Wu C-Y, Jan J-T, Ma S-H, et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci U S A 2004;101:10012-10017.
8. 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.
9. 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.
10. Kim UJ, Won E-J, Kee S-J, Jung S-I, Jang H-C. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther 2016;21:455-459.
11. 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.
12. Min C-K, Cheon S, Ha N-Y, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 2016;6:25359-25359.
13. 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.
14. 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.
15. 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.
16. International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) home page (https://isaric.tghn.org/. opens in new tab).
17. Wang Y, Fan G, Salam A, et al. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J Infect Dis 2019 December 11 (Epub ahead of print).
18. Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization (http://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus/en/. opens in new tab).
19. National Early Warning Score (NEWS) 2: standardising the assessment of acute-illness severity in the NHS. London: Royal College of Physicians, 2017 (https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2. opens in new tab).
20. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406.
21. 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.
22. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012;55:1198-1204.
23. 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.
24. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020 March 11 (Epub ahead of print).
25. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.
26. Yamamoto N, Yang R, Yoshinaka Y, et al. HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus. Biochem Biophys Res Commun 2004;318:719-725.
洛匹那韦-利托那韦治疗重症新型冠状病毒肺炎研究后记
曹彬1*，王业明1，范国辉1，张定宇2*，王辰1*
1中日友好医院呼吸中心，国家呼吸疾病临床研究中心，中国医学科学院呼吸病学研究院
2武汉金银潭医院
*通讯作者
2020年1月9日通过伦理审查至3月初完成随访，团队立刻将结果向国家卫生健康委员会（以下简称卫健委）等主管部门汇报。卫健委科教司组织专家评审，高度肯定了本次临床试验的意义，认为本研究为新冠（COVID-19）重症临床救治提供了直接依据。此外，洛匹那韦-利托那韦被世界卫生组织列为应对COVID-19全球研发蓝图计划的亟待评估药物之一。世界卫生组织高度关注研究进展，并多次致电询问研究主要结果。
查看更多