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.).
N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao) to the fraction of inspired oxygen (Fio) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
背景：目前尚无针对由 SARS-CoV-2 引起的重症疾病的有效治疗方法。
方法：我们开展了一项随机、对照、开放性标签试验，纳入了因 SARS-CoV-2 感染而住院的成年患者，这些患者患有导致呼吸道疾病的 COVID-19，并且在呼吸环境空气时血氧饱和度（Sao）为 94%或以下，或者氧分压（Pao）与吸入氧分数（Fio）的比值小于 300mmHg。患者按 1:1 的比例随机分为洛匹那韦-利托那韦（分别为 400mg 和 100mg）组和标准治疗组，每天两次，共 14 天，同时接受标准治疗。主要终点是临床改善时间，定义为从随机分组到以下任意一个时间点的时间：7 级分类量表上的评分提高 2 分，或者从医院出院。
结果：共有 199 例经实验室确诊的 SARS-CoV-2 感染患者接受了随机分组；其中 99 例患者分入洛匹那韦-利托那韦组，100 例患者分入标准治疗组。与标准治疗相比，洛匹那韦-利托那韦治疗与临床改善时间无差异（临床改善的风险比为 1.31；95%置信区间[CI]，0.95 至 1.80）。28 天死亡率在洛匹那韦-利托那韦组和标准治疗组相似（19.2% vs. 25.0%；差值为-5.8 个百分点；95%CI，-17.3 至 5.7）。在不同时间点检测到病毒 RNA 的患者比例相似。在改良意向治疗分析中，与标准治疗相比，洛匹那韦-利托那韦组的临床改善中位时间缩短了 1 天（风险比，1.39；95%CI，1.00 至 1.91）。洛匹那韦-利托那韦组更常见胃肠道不良事件，但标准治疗组更常见严重不良事件。由于不良事件，共有 13 名（13.8%）患者提前停止了洛匹那韦-利托那韦治疗。
结论：在患有严重 COVID-19 的住院成年患者中，洛匹那韦-利托那韦治疗并未带来优于标准治疗的临床获益。针对重症患者的未来临床试验可能有助于证实或排除治疗获益的可能性。（由新药创制重大专项和其他项目资助；中国临床试验注册中心编号，ChiCTR2000029308。）
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