Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial

Yueping Li, Zhiwei Xie, Weiyin Lin, Weiping Cai, Chunyan Wen, Yujuan Guan, Xiaoneng Mo, Jian Wang, Yaping Wang, Ping Peng, Xudan Chen, Wenxin Hong, Guangming Xiao, Jinxin Liu, Lieguang Zhang, Fengyu Hu, Feng Li, Fuchun Zhang, Xilong Deng, Linghua Li, Yueping Li, Zhiwei Xie, Weiyin Lin, Weiping Cai, Chunyan Wen, Yujuan Guan, Xiaoneng Mo, Jian Wang, Yaping Wang, Ping Peng, Xudan Chen, Wenxin Hong, Guangming Xiao, Jinxin Liu, Lieguang Zhang, Fengyu Hu, Feng Li, Fuchun Zhang, Xilong Deng, Linghua Li

Abstract

Background: Antiviral therapies against the novel coronavirus SARS-CoV-2, which has caused a global pandemic of respiratory illness called COVID-19, are still lacking.

Methods: Our study (ClinicalTrials.gov: NCT04252885, named ELACOI), was an exploratory randomized (2:2:1) controlled trial assessing the efficacy and safety of lopinavir/ritonavir (LPV/r) or arbidol monotherapy for treating patients with mild/moderate COVID-19.

Findings: This study successfully enrolled 86 patients with mild/moderate COVID-19, with 34 randomly assigned to receive LPV/r, 35 to arbidol, and 17 with no antiviral medication as control. Baseline characteristics of the three groups were comparable. The primary endpoint, the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid, was similar between groups (all p > 0.05). There were no differences between groups in the secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of chest computed tomography (CT) at days 7 or 14 (all p > 0.05). At day 7, 8 (23.5%) patients in the LPV/r group, 3 (8.6%) in the arbidol group, and 2 (11.8%) in the control group showed a deterioration in clinical status from moderate to severe/critical (p = 0.206). Overall, 12 (35.3%) patients in the LPV/r group and 5 (14.3%) in the arbidol group experienced adverse events during the follow-up period. No apparent adverse event occurred in the control group.

Conclusions: LPV/r or arbidol monotherapy present little benefit for improving the clinical outcome of patients hospitalized with mild/moderate COVID-19 over supportive care.

Funding: This study was supported by project 2018ZX10302103-002, 2017ZX10202102-003-004, and Infectious Disease Specialty of Guangzhou High-level Clinical Key Specialty (2019-2021).

Keywords: COVID-19; SARS-CoV-2; arbidol; efficacy; lopinavir/ritonavir.

Conflict of interest statement

The authors declare no competing interests.

© 2020 Published by Elsevier Inc.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Trial Profile θSAE, severe adverse event; φ LPV/r: lopinavir/ritonavir.
Figure 2
Figure 2
Rate of Positive-to-Negative Conversion of SARS-CoV-2 Nucleic Acid Detected from Pharyngeal Swabs in Each of the Three Treatment Groups during the 21-day Follow-Up Period LPV/r, lopinavir/ritonavir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 3
Figure 3
Proportion of Patients in Each of the Three Treatment Groups with Positive SARS-CoV-2 Nucleic Acid during the 21-Day Follow-Up Period LPV/r, lopinavir/ritonavir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

References

    1. Wang Z., Yang B., Li Q., Wen L., Zhang R. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin. Infect. Dis. 2020 doi: 10.1093/cid/ciaa272. Published online March 16, 2020.
    1. Who Health Organization . 2020. Coronavirus disease 2019 (COVID-19) Situation Report –71.
    1. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H., Wang W., Song H., Huang B., Zhu N. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–574.
    1. Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H., Wu Y., Zhang L., Yu Z., Fang M. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med. 2020;8:475–481. doi: 10.1016/S2213-2600(20)30079-5.
    1. National Health Commission of China. (2020). Diagnosis and treatment of pneumonia caused by new coronavirus (trial version 6). .
    1. Mangum E.M., Graham K.K. Lopinavir-Ritonavir: a new protease inhibitor. Pharmacotherapy. 2001;21:1352–1363.
    1. Pasquau J., Hidalgo-Tenorio C., Montes M.L., Romero-Palacios A., Vergas J., Sanjoaquín I., Hernández-Quero J., Aguirrebengoa K., Orihuela F., Imaz A., QoLKAMON STUDY GROUP High quality of life, treatment tolerability, safety and efficacy in HIV patients switching from triple therapy to lopinavir/ritonavir monotherapy: A randomized clinical trial. PLoS ONE. 2018;13:e0195068.
    1. Sheahan T.P., Sims A.C., Leist S.R., Schäfer A., Won J., Brown A.J., Montgomery S.A., Hogg A., Babusis D., Clarke M.O. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020;11:222.
    1. Chan K.S., Lai S.T., Chu C.M., Tsui E., Tam C.Y., Wong M.M., Tse M.W., Que T.L., Peiris J.S., Sung J. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med. J. 2003;9:399–406.
    1. Brooks M.J., Burtseva E.I., Ellery P.J., Marsh G.A., Lew A.M., Slepushkin A.N., Crowe S.M., Tannock G.A. Antiviral activity of arbidol, a broad-spectrum drug for use against respiratory viruses, varies according to test conditions. J. Med. Virol. 2012;84:170–181.
    1. Popov A.F., Simakova A.I., Dmitrenko K.A., Shchelkanov M.Y. [Time course of changes in cytokines (IFN-γ, IFN-α, IL-18, TNF-α) in the treatment of moderate influenza A (H1N1) pdm09 (2013-2016) with oseltamivir (Tamiflu) and umifenovir (Arbidol) alone and in combination with Kagocel] Ter. Arkh. 2017;89:66–70.
    1. Leneva I.A., Falynskova I.N., Makhmudova N.R., Poromov A.A., Yatsyshina S.B., Maleev V.V. Umifenovir susceptibility monitoring and characterization of influenza viruses isolated during ARBITR clinical study. J. Med. Virol. 2019;91:588–597.
    1. Khamitov R.A., Loginova S.Ia., Shchukina V.N., Borisevich S.V., Maksimov V.A., Shuster A.M. [Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures] Vopr. Virusol. 2008;53:9–13.
    1. Zhang Q., Wang Y., Qi C., Shen L., Li J. Clinical trial analysis of 2019-nCoV therapy registered in China. J. Med. Virol. 2020 doi: 10.1002/jmv.25733. Published online February 28, 2020.
    1. Jin Y.H., Cai L., Cheng Z.S., Cheng H., Deng T., Fan Y.P., Fang C., Huang D., Huang L.Q., Huang Q., for the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team, Evidence-Based Medicine Chapter of China International Exchange and Promotive Association for Medical and Health Care (CPAM) A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Mil. Med. Res. 2020;7:4.
    1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., Wang B., Xiang H., Cheng Z., Xiong Y. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 doi: 10.1001/jama.2020.1585. Published online February 7, 2020.
    1. Lai C.C., Shih T.P., Ko W.C., Tang H.J., Hsueh P.R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int. J. Antimicrob. Agents. 2020;55:105924.
    1. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G., Ruan L., Song B., Cai Y., Wei M. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N. Engl. J. Med. 2020;382:1787–1799.
    1. Chen J., Ling Y., Xi X., Liu P., Li F., Li T., Shang Z., Wang M., Shen Y., Lu H. Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia. Chin J Epidemiol. 2020;38 doi: 10.3760/cma.j.cn311365-20200210-00050.
    1. Chen W., Lan Y., Yuan X., Deng X., Li Y., Cai X., Li L., He R., Tan Y., Deng X. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg. Microbes Infect. 2020;9:469–473.

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