A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19
Authors: Lihong Pan
Thomas Jaki
Jing Wu
Jiuyang Xu
Danning Wen
Li Guo
Qin Ge
Xuelei Xie
Xia Zhou
Xingwang Li
Tao Bai
Jing He
Ye Yuan
Guohui Fan
Lianguo Ruan
Haiyan Zhan
Lianhan Shang
Shengjing Tu
Xiaoying Gu
Jie Xiang
Nanshan Chen
Frederick G Hayden
Ting Yu
Chen Wang
Caihong Li
Lu Peng
Wen Liu
Fengyun Gong
Ming Wei
Sixia Lu
Fang Qiu
Jiaan Xia
Hui Li
Xudong Wu
Li Zhang
Peter W Horby
Chunmin Jia
Xuan Dong
Fang Cheng
Huadong Li
Xia Liu
Yeming Wang
Chaolin Huang
Fei Zhou
Hanping Huang
Dingyu Zhang
Yanping Cai
Chongya Dong
Bin Song
Ying Liu
Zhibo Liu
Shanshan Luo
Jingli Wang
Hua Chen
Yi Zhang
Jun Zou
Xujuan Hu
Kunxia Li
Juan Wang
Ke Wang
Bin Cao
Yuan Wei
Shuzhen Wang
Zhaohui Qu
Shunan Ruan
Journal: New England Journal of Medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: therapeutics; SARS-CoV-2; Covid-19; lopinavir-ritonavir; clinical improvement
Affiliations: 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.).

Abstract:  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 (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) 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.). 

Retracted: No

PubPeer comments:
 There are many concerns about the integrity of 172 publications by this research group, including this one. Some of the concerns are published 1. Anaesthesia 2020;75:1683u201392, see Supplementary data. This paper is A44 2. Account Res 2020;28:149-61. 3. J Clin Epidemiol 2021;131:22-29. Journals and publishers were notified of these concerns in July 2019. 23 publications have an expression of concern. To our knowledge there has been no public response about any of the concerns. We think these publications are unreliable , 
 September 2, 2020 u201cWith this notice, Frontiers states its awareness of concerns regarding the validity of the participant data in this study. An investigation is currently being conducted by Kashan University of Medical Sciences research ethics committee. This expression of concern has been posted while Frontiers awaits the outcome of that investigation and will then be updated accordingly.u201d ,