Antiviral treatment selection for SARS-CoV-2 pneumonia

ABSTRACT Introduction Therapy of coronavirus disease 2019 (COVID-19) involves evolving algorithms that include drugs aimed at reducing disease progression by counteracting two different, but intertwined processes: (i) the damage caused by the virus (with antivirals); (ii) the damage caused by a dysregulated host response (with immunomodulatory agents). Areas covered Herein, we discuss the available evidence on the efficacy and safety of antiviral agents employed over the past months for the treatment of COVID-19, and the reasons to be considered for antiviral selection. Expert opinion The available evidence from randomized controlled trials (RCT) currently discourages the use of lopinavir/ritonavir, hydroxychloroquine, and interferons, which did not show improved efficacy compared to standard care or placebo. Regarding remdesivir, the current body of evidence may conditionally support its use in COVID-19 patients requiring oxygen supplementation but still not requiring invasive mechanical ventilation. Finally, neutralizing monoclonal antibodies have been proven efficacious in reducing the risk of severe disease development if administered early in the course of the disease to patients at risk of progression. The results of the ongoing RCT will certainly be crucial to further improve our understanding of the optimal place in therapy of antiviral agents for COVID-19.

[1]  P. Taylor,et al.  Neutralizing monoclonal antibodies for treatment of COVID-19 , 2021, Nature Reviews Immunology.

[2]  A. Simonds,et al.  Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline , 2021, European Respiratory Journal.

[3]  D. Ho,et al.  Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 , 2021, Nature.

[4]  S. de Lusignan,et al.  Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial , 2021, The Lancet.

[5]  G. Piccialli,et al.  Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses , 2021, Molecules.

[6]  M. Peana,et al.  Chloroquine and hydroxychloroquine in the treatment of COVID-19: the never-ending story , 2021, Applied Microbiology and Biotechnology.

[7]  P. Pelosi,et al.  Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies , 2021, Frontiers in Physiology.

[8]  D. Skovronsky,et al.  Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. , 2021, JAMA.

[9]  John D. Davis,et al.  REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19 , 2020, The New England journal of medicine.

[10]  H. Keyvani,et al.  Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial , 2020, BMC Infectious Diseases.

[11]  P. Hotez,et al.  Neutralizing antibodies for the treatment of COVID-19 , 2020, Nature Biomedical Engineering.

[12]  C. Caracta,et al.  Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial , 2020, International Journal of Infectious Diseases.

[13]  Dave Singh,et al.  Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial , 2020, The Lancet Respiratory Medicine.

[14]  I. Al-Zakwani,et al.  Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia , 2020, International Journal of Infectious Diseases.

[15]  A. F. Erdem,et al.  Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID‐19 , 2020, Journal of clinical pharmacy and therapeutics.

[16]  J. Noh,et al.  Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study , 2020, International Journal of Infectious Diseases.

[17]  R. Malekzadeh,et al.  Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results , 2020, medRxiv.

[18]  Jennifer L. Bell,et al.  Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial , 2020, The Lancet.

[19]  Dong Zhao,et al.  Treatment of COVID-19 Patients with Prolonged Post-Symptomatic Viral Shedding with Leflunomide -- a Single-Center, Randomized, Controlled Clinical Trial , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  O. Tsang,et al.  Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. , 2020, JAMA.

[21]  T. Fiolet,et al.  Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis , 2020, Clinical Microbiology and Infection.

[22]  A. Davarpanah,et al.  Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial , 2020, The Journal of antimicrobial chemotherapy.

[23]  S. Merat,et al.  Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial , 2020, The Journal of antimicrobial chemotherapy.

[24]  E. Calzolari,et al.  Clinical characteristics, management and in-hospital mortality of patients with coronavirus disease 2019 in Genoa, Italy , 2020, Clinical Microbiology and Infection.

[25]  S. Abd-Elsalam,et al.  Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study , 2020, The American journal of tropical medicine and hygiene.

[26]  N. Savchuk,et al.  AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  A. Ivashchenko,et al.  AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial , 2020 .

[28]  P. Niu,et al.  SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial , 2020, International Journal of Infectious Diseases.

[29]  S. Tavakolpour,et al.  Remdesivir: A beacon of hope from Ebola virus disease to COVID‐19 , 2020, Reviews in medical virology.

[30]  Á. Avezum,et al.  Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 , 2020, The New England journal of medicine.

[31]  Zhihai Chen,et al.  Brief Report: Retrospective Evaluation on the Efficacy of Lopinavir/Ritonavir and Chloroquine to Treat Nonsevere COVID-19 Patients , 2020, Journal of acquired immune deficiency syndromes.

[32]  K. Kalantar-Zadeh,et al.  Pharmaco-Immunomodulatory Therapy in COVID-19 , 2020, Drugs.

[33]  Inge Christoffer Olsen,et al.  A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics , 2020, Nature Communications.

[34]  Lidia Ruiz,et al.  Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[35]  Jennifer L. Bell,et al.  Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. , 2020, medRxiv.

[36]  M. Murad,et al.  Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis , 2020, medRxiv.

[37]  S. Goutelle,et al.  Azithromycin for COVID-19: More Than Just an Antimicrobial? , 2020, Clinical Drug Investigation.

[38]  S. Anzick,et al.  Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 , 2020, Nature.

[39]  Kecheng Zhang,et al.  Lopinavir/ritonavir and interferon combination therapy may help shorten the duration of viral shedding in patients with COVID‐19: A retrospective study in two designated hospitals in Anhui, China , 2020, Journal of medical virology.

[40]  R. Bruno,et al.  Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 , 2020, The New England journal of medicine.

[41]  P. Pelosi,et al.  A brief note on randomized controlled trials and compassionate/off-label use of drugs in the early phases of the COVID-19 pandemic , 2020, Drugs in context.

[42]  Eun Ji Kim,et al.  Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets , 2020, mBio.

[43]  L. Dodd,et al.  Remdesivir for the Treatment of Covid-19 — Final Report , 2020, The New England journal of medicine.

[44]  J. Qu,et al.  Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial , 2020, BMJ.

[45]  David R. Holtgrave,et al.  Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State , 2020, The Journal of Emergency Medicine.

[46]  P. Pelosi,et al.  Distinct phenotypes require distinct respiratory management strategies in severe COVID-19 , 2020, Respiratory Physiology & Neurobiology.

[47]  G. Hripcsak,et al.  Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 , 2020, The New England journal of medicine.

[48]  Zhìhóng Hú,et al.  The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro , 2020, Cell Discovery.

[49]  Kwok-Hung Chan,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 , 2020, The Lancet.

[50]  Yi Wang,et al.  Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial , 2020, The Lancet.

[51]  L. Richeldi,et al.  Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) , 2020, Clinical Microbiology and Infection.

[52]  J. Huang,et al.  Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study , 2020, Clinical Microbiology and Infection.

[53]  S. Anzick,et al.  Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 , 2020, Nature.

[54]  Jenny Y. Zhang,et al.  Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19) , 2020, Journal of Translational Medicine.

[55]  A. Elfiky,et al.  Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study , 2020, Life Sciences.

[56]  A. Kalil Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. , 2020, JAMA.

[57]  D. Raoult,et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial , 2020, International Journal of Antimicrobial Agents.

[58]  Yuan Wei,et al.  A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 , 2020, The New England journal of medicine.

[59]  Wu Zhong,et al.  Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study , 2020, Engineering.

[60]  Xiu-Jie Wang,et al.  Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines , 2020, Journal of Genetics and Genomics.

[61]  Gengfu Xiao,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[62]  Y. Furuta,et al.  Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase , 2017, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[63]  Lisa E. Gralinski,et al.  Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses , 2017, Science Translational Medicine.

[64]  A. Lew,et al.  Antiviral activity of arbidol, a broad‐spectrum drug for use against respiratory viruses, varies according to test conditions , 2012, Journal of medical virology.

[65]  V. Lee,et al.  Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors , 2008, Journal of Theoretical Biology.

[66]  S. Polyak,et al.  Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. , 2008, Current medicinal chemistry.

[67]  Y. Guan,et al.  Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings , 2004, Thorax.

[68]  V. Wong,et al.  Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. , 2003, Hong Kong medical journal = Xianggang yi xue za zhi.

[69]  V. A. Maksimov,et al.  [Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures]. , 2008, Voprosy virusologii.