Early administration of #lopinavir/ritonavir plus #hydroxychloroquine does not alter the #clinical #course of #SARS‐CoV‐2 infection: a retrospective cohort study (J Med Virol., abstract)

[Source: Journal of Medical Virology, full page: (LINK). Abstract, edited.]

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS‐CoV‐2 infection: a retrospective cohort study

Andrea Giacomelli MD,  Gabriele Pagani MD,  Anna Lisa Ridolfo MD,  Letizia Oreni BIT, Federico Conti MD,  Laura Pezzati MD,  Lucia Bradanini MD,  Giacomo Casalini MD, Cinzia Bassoli MD,  Valentina Morena MD,  Simone Passerini MD,  Giuliano Rizzardini MD,  Chiara Cogliati MD,  Elisa Ceriani MD,  Riccardo Colombo MD,  Stefano Rusconi MD, Cristina Gervasoni MD,  Dario Cattaneo PharmD PhD,  Spinello Antinori MD,  Massimo Galli MD

First published: 10 August 2020 | DOI:  https://doi.org/10.1002/jmv.26407

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26407

 

ABSTRACT

Background

As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID‐19 during the first wave of the epidemic in Lombardy, Italy.

Methods

To compare the rate of clinical improvement between those who started LPV/ritonavir (LPV/r)+HCQ within five days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). This was a retrospective intent‐to‐treat analysis of the hospitalized patients who started LPV/r+HCQ between 21 February and 20 March 2020. The association between the timing of treatment and the probability of 30‐day mortality was assessed using uni‐ and multivariable logistic models.

Results

The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray’s test P =0.213). After adjusting for potentially relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30‐day mortality (adjusted odds ratio [aOR] ET vs DT=1.45, 95% confidence interval 0.50‐4.19). Eight percent of the patients discontinued the treatment because of severe gastrointestinal disorders attributable to LPV/r.

Conclusion

The timing of the start of LPV/r+HCQ treatment does not seem to affect the clinical course of hospitalised patients with COVID‐19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID‐19.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Lopinavir; Ritonavir; Chloroquine.

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#AVIFAVIR for #Treatment of Patients with #Moderate #COVID19: Interim #Results of a Phase II/III Multicenter #RCT (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial

Andrey A Ivashchenko, Kirill A Dmitriev, Natalia V Vostokova, Valeria N Azarova, Andrew A Blinow, Alina N Egorova, Ivan G Gordeev, Alexey P Ilin, Ruben N Karapetian, Dmitry V Kravchenko, Nikita V Lomakin, Elena A Merkulova, Natalia A Papazova, Elena P Pavlikova, Nikolay P Savchuk, Elena N Simakina, Tagir A Sitdekov, Elena A Smolyarchuk, Elena G Tikhomolova, Elena V Yakubova, Alexandre V Ivachtchenko

Clinical Infectious Diseases, ciaa1176, https://doi.org/10.1093/cid/ciaa1176

Published: 09 August 2020

 

Abstract

In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the pilot stage of Phase II/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days, and was safe and well-tolerated.

AVIFAVIR, favipiravir, COVID-19, SARS-CoV-2

Issue Section: Brief Report

This content is only available as a PDF.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords: SARS-CoV-2; COVID-19; Antivirals; Favipiravir.

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#Inhibition of PIKfyve #kinase prevents infection by Zaire #ebolavirus and #SARS-CoV-2 (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2

Yuan-Lin Kang, Yi-ying Chou,  Paul W. Rothlauf,  Zhuoming Liu, Timothy K. Soh,  David Cureton, James Brett Case, Rita E. Chen,  Michael S. Diamond,  Sean P. J. Whelan, and  Tom Kirchhausen

PNAS first published August 6, 2020 | DOI: https://doi.org/10.1073/pnas.2007837117

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved July 22, 2020 (received for review April 22, 2020)

 

Significance

The membrane fusion proteins of viral pathogens as diverse in their replication strategies as coronaviruses and filoviruses depend, for their functional activity, on proteolytic processing during cell entry. Endosomal cathepsins carry out the cleavages. We have constructed chimeric forms of vesicular stomatitis virus (VSV) bearing the fusion proteins of Zaire ebolavirus (ZEBOV) or SARS coronavirus 2 (SARS-CoV-2) and shown that two small-molecule inhibitors of an endosomal lipid kinase (PIKfyve) inhibit viral infection by preventing release of the viral contents from endosomes. Both inhibitory compounds cause distension of Rab5 and Rab7 subcompartments into small vacuoles. One of them (Apilimod) also inhibits infection of cells by authentic SARS-CoV-2. The results point to possibilities for host targets of antiviral drugs.

 

Abstract

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric vesicular stomatitis virus (VSV) containing the envelope proteins of Zaire ebolavirus (VSV-ZEBOV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small-molecule inhibitors of the main endosomal phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing small-molecule antivirals against SARS-CoV-2.

COVID-19 – SARS-CoV-2 – ZEBOV – APILIMOD – Vacuolin-1

 

Footnotes

1 Present address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.

2 Present address: Biogen, Cambridge, MA 02142.

3 To whom correspondence may be addressed. Email: spjwhelan@wustl.edu or kirchhausen@crystal.harvard.edu.

Author contributions: M.S.D., S.P.J.W., and T.K. designed research; Y.-L.K., Y.-y.C., P.W.R., Z.L., J.B.C., and R.E.C. performed research; Y.-L.K., Y.-y.C., T.K.S., and D.C. contributed new reagents/analytic tools; Y.-L.K. and T.K. analyzed data; T.K. wrote the paper; and T.K. supervised the project.

Competing interest statement: M.S.D. is a consultant for Inbios, Vir Biotechnology, and NGM Biopharmaceuticals, and is on the Scientific Advisory Board of Moderna. The M.S.D. laboratory at Washington University School of Medicine has received sponsored research agreements from Moderna and Emergent BioSolutions.

This article is a PNAS Direct Submission. This article contains supporting information online  at  https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2007837117/-/DCSupplemental

Keywords: SARS-CoV-2; Zaire Ebolavirus; Antivirals.

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A Randomized Trial of #Hydroxychloroquine as #Postexposure #Prophylaxis for #Covid19 (N Engl J Med., abstract)

[Source: The New England Journal of Medicine, full page: (LINK). Abstract, edited.]

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

David R. Boulware, M.D., M.P.H., Matthew F. Pullen, M.D., Ananta S. Bangdiwala, M.S., Katelyn A. Pastick, B.Sc., Sarah M. Lofgren, M.D., Elizabeth C. Okafor, B.Sc., Caleb P. Skipper, M.D., Alanna A. Nascene, B.A., Melanie R. Nicol, Pharm.D., Ph.D., Mahsa Abassi, D.O., M.P.H., Nicole W. Engen, M.S., Matthew P. Cheng, M.D., et al.

 

Abstract

BACKGROUND

Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.

RESULTS

We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.

CONCLUSIONS

After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668. opens in new tab.)

Keywords: SARS-CoV-2; COVID-19; Antivirals; Chloroquine.

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#Remdesivir Use Compared to Supportive Care in Hospitalized Patients with #Severe #COVID19: A Single-Center Experience (Open Forum Infect Dis., abstract)

[Source: Open Forum Infectious Diseases, full page: (LINK). Abstract, edited.]

Remdesivir Use Compared to Supportive Care in Hospitalized Patients with Severe COVID-19: A Single-Center Experience

Markos Kalligeros, Karen T Tashima, Evangelia K Mylona, Natasha Rybak, Timothy P Flanigan, Dimitrios Farmakiotis, Curt G Beckwith, Martha Sanchez, Marguerite Neill, Jennie E Johnson, Joseph M Garland, Su Aung, Katrina M Byrd, Thomas O’Brien, Aakriti Pandita, Jad Aridi, Raul Macias Gil, Jerome Larkin, Fadi Shehadeh, Eleftherios Mylonakis

Open Forum Infectious Diseases, ofaa319, https://doi.org/10.1093/ofid/ofaa319

Published: 06 August 2020

 

Abstract

Background

The US Food and Drug Administration issued an Emergency Use Authorization for remdesivir use in patients with severe COVID-19.

Methods

We utilized data from two quaternary, acute care hospitals. The outcomes of interest were the impact of remdesivir on in-hospital death by day 28 as well as time to recovery, clinical improvement, and discharge. We utilized Cox proportional hazards models and stratified log-rank tests.

Results

224 patients were included in the study. Median age was 59 years; 67.0% were male; 17/125 patients (13.6%) who received supportive care and 7/99 patients (7.1%) who received remdesivir died. The unadjusted risk for 28-day in-hospital death was lower for patients who received remdesivir compared to patients who received supportive care (HR 0.42; 95% CI: 0.16-1.08). Although this trend remained the same after adjusting for age, sex, race and oxygen requirements on admission (aHR 0.49; 95% CI: 0.19-1.28), as well as chronic comorbidities and use of corticosteroids (aHR 0.44; 95% CI: 0.16-1.23), it did not reach statistical significance. The use of remdesivir was not associated with an increased risk of acute kidney injury (AKI) and liver test abnormalities. Although not statistically significant, the rate ratios for time to recovery, clinical improvement, and discharge were higher in women and Black or African American patients.

Conclusion

Patients on remdesivir had lower, albeit not significant, all-cause in hospital mortality, and the use of remdesivir did not increase the risk for AKI. Promising signals from this study need to be confirmed by future placebo-controlled randomized clinical trials.

COVID-19, SARS-CoV-2, remdesivir, efficacy, safety

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords: SARS-CoV-2; COVID-19; Antivirals; Remdesivir.

——

#Atazanavir, alone or in combination with #ritonavir, inhibits #SARS-CoV-2 #replication and pro-inflammatory #cytokine production (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Natalia Fintelman-Rodrigues, Carolina Q. Sacramento, Carlyle Ribeiro Lima, Franklin Souza da Silva, André C. Ferreira, Mayara Mattos, Caroline S. de Freitas, Vinicius Cardoso Soares, Suelen da Silva Gomes Dias, Jairo R. Temerozo, Milene D. Miranda, Aline R. Matos, Fernando A. Bozza, Nicolas Carels, Carlos Roberto Alves, Marilda M. Siqueira, Patrícia T. Bozza, Thiago Moreno L. Souza

DOI: 10.1128/AAC.00825-20

 

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of IL-6 and TNF-α levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Cytokines; Atazanavir; Ritonavir.

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#SARS-CoV-2 RNA Dependent RNA polymerase (#RdRp) – A #drug #repurposing study (Heliyon, abstract)

[Source: Heliyon, full page: (LINK). Abstract, edited.]

SARS-CoV-2 RNA Dependent RNA polymerase (RdRp) – A drug repurposing study

Jamshaid Ahmad, Saima Ikram, Fawad Ahmad, Irshad Ur Rehman, Maryam Mushtaq

Open Access | Published: July 23, 2020 | DOI: https://doi.org/10.1016/j.heliyon.2020.e04502

 

Abstract

The outbreak of SARS-CoV-2 in December 2019 in China subsequently lead to a pandemic. Lack of vaccine and specific anti-viral drugs started a global health disaster. For a sustained control and protection, development of potential anti-viral drugs is one of the targeted approach. Although, designing and developing a panel of new drugs molecules are always encouraged. However, in the current emergency, drug repurposing study is one of the most effective and fast track option. The crystal structure of a SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) RNA Dependent RNA Polymerase (RdRp) has recently been deciphered through X-ray crystallography. The single-chain of core RNA Dependent RNA Polymerase relies on virus-encoded cofactors nsp7 and two units of nsp8 for its optimum function. This study explored the FDA approved database of 7922 molecules and screened against the core polymerase along with cofactors. Here we report a panel of FDA approved drugs that show substantial interactions with key amino acid residues of the active site. Interestingly, some of the identified drugs (Ornipressin, Lypressin, Examorelin, Polymyxin B1) bind strongly within the binding pockets of both forms of RdRp. Besides, we found strong candidates for the complex form as well which include Nacortocin, Cistinexine, Cisatracurium (among others). These drugs have the potential to be considered while contriving therapeutic options.

Keywords: SARS-CoV-2; COVID-19; Antivirals.

——

#Functional #neuraminidase #inhibitor #resistance motifs in #avian #influenza A(#H5Nx) viruses (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 1 August 2020, 104886 | In Press, Journal Pre-proof | Research paper

Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses

Dagmara Bialy, Holly Shelton, The Pirbright Institute, Pirbright, United Kingdom

Received 24 March 2020, Revised 13 July 2020, Accepted 16 July 2020, Available online 1 August 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104886

 

Highlights

  • A R292K residue change in NA reduces susceptibility to NA inhibitor drugs (NAIs) in H5N6 and H5N2 avian influenza viruses.
  • All four mutations (E119V, H274Y, R292K and N294S) reducing susceptibility to NAIs in H5N6 viruses also reduced viral NA activity.
  • Reduced susceptibility to NA inhibitors in H5N6 did not attenuate virus replication efficiency in chicken cells or eggs.
  • A reduction of the viral HA affinity for sialic acid was observed in H5N6 viruses with reduced NA activity.

 

Abstract

Neuraminidase inhibitors (NAIs) are antiviral agents recommended worldwide to treat or prevent influenza virus infections in humans. Past influenza virus pandemics seeded by zoonotic infection by avian influenza viruses (AIV) as well as the increasing number of human infections with AIV have shown the importance of having information about resistance to NAIs by avian NAs that could cross the species barrier. In this study we introduced four NAI resistance-associated mutations (N2 numbering) previously found in human infections into the NA of three current AIV subtypes of the H5Nx genotype that threaten the poultry industry and human health: highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we showed that a R292K substitution in H5N6 and H5N2 viruses significantly reduced susceptibility to three licenced NAIs: oseltamivir, zanamivir and peramivir. In contrast the mutations E119V, H274Y and N294S had more variable effects with NAI susceptibility being drug- and strain-specific. We measured the replicative fitness of NAI resistant H5N6 viruses and found that they replicated to comparable or significantly higher titres in primary chicken cells and in embryonated hens’ eggs as compared to wild type – despite the NA activity of the viral neuraminidase proteins being reduced. The R292K and N294S drug resistant H5N6 viruses had single amino acid substitutions in their haemagglutinin (HA): Y98F and A189T, respectively (H3 numbering) which reduced receptor binding properties possibly balancing the reduced NA activity seen. Our results demonstrate that the H5Nx viruses can support drug resistance mutations that confer reduced susceptibility to licenced NAIs and that these H5N6 viruses did not show diminished replicative fitness in avian cell cultures. Our results support the requirement for on-going surveillance of these strains in bird populations to include motifs associated with human drug resistance.

Keywords: Avian Influenza; H5N2; H5N6; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

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The #Multidimensional #Challenge of Treating #COVID19: #Remdesivir is a Foot in the Door (Clin Infect Dis., summary)

[Source: Clinical Infectious Diseases, full page: (LINK). Summary, edited.]

The Multidimensional Challenge of Treating COVID-19: Remdesivir is a Foot in the Door

Rajesh T. Gandhi, M.D., Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Corresponding Author: Rajesh T. Gandhi, MD., Massachusetts General Hospital, GRJ 504,  55 Fruit St, Boston, MA 02114 – T: 617-724-9690; F: 617-726-7653; Email: rgandhi@mgh.harvard.edu

Downloaded from https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/ciaa1132/5879440 by guest on 01 August 2020

Accepted Manuscript

___

There are multiple dimensions to consider when treating COVID-19: the severity of  infection, the goals of treatment, and the intervention being deployed. Most people with  symptomatic SARS CoV-2 infection have mild or moderate disease but early estimates  from China were that 15% develop severe disease and 5% have critical illness [1, 2]. The  goals of treatment depend in part on severity of disease. In people who have mild  disease, who are typically managed as outpatients, the goal is to prevent progression and hospitalization. In people who are hospitalized, the goal is to hasten recovery and  prevent complications and death. A third dimension of treating COVID-19 is the specific  intervention, which are sometimes grouped into categories: antiviral medications;  treatments that enhance antiviral immunity; and antiinflammatories or immune  modulators. The multidimensional challenge of treating COVID-19 can be  simply  formulated as: What are the best interventions to meet the goals of treating COVID-19 in
differing severities of disease?

(…)

Keywords: SARS-CoV-2; COVID-19; Antivirals; Immunomodulators; Remdesivir; Tocilizumab.

—–

#Drug #treatments for #covid19: living systematic #review and network meta-analysis (BMJ, abstract)

[Source: British Medical Journal, full page: (LINK). Abstract, edited.]

Drug treatments for covid-19: living systematic review and network meta-analysis

BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2980 (Published 30 July 2020)

Cite this as: BMJ 2020;370:m2980

Reed AC Siemieniuk , methodologist, internist1 *,  Jessica J Bartoszko, methodologist1 *,  Long Ge, methodologist2 *,  Dena Zeraatkar, methodologist1 *,  Ariel Izcovich, methodologist, internist3,  Hector Pardo-Hernandez, methodologist45,  Bram Rochwerg, methodologist, critical care physician16,  Francois Lamontagne, methodologist, critical care physician7,  Mi Ah Han, methodologist8,  Elena Kum, methodologist1,  Qin Liu, professor910,  Arnav Agarwal, methodologist, internist111,  Thomas Agoritsas, methodologist, internist112,  Paul Alexander, methodologist, assistant professor1,  Derek K Chu, methodologist, immunologist16,  Rachel Couban, librarian13,  Andrea Darzi, methodologist1,  Tahira Devji, methodologist1,  Bo Fang, methodologist910,  Carmen Fang, registered nurse14,  Signe Agnes Flottorp, senior researcher1516,  Farid Foroutan, methodologist117,  Diane Heels-Ansdell, statistician1,  Kimia Honarmand, methodologist, critical care physician3,  Liangying Hou, medical doctor candidate2,  Xiaorong Hou, librarian18,  Quazi Ibrahim, statistician1,  Mark Loeb, methodologist, infectious disease physician16,  Maura Marcucci, methodologist, internist16,  Shelley L McLeod, methodologist, assistant professor1920,  Sharhzad Motaghi, methodologist1,  Srinivas Murthy, clinical associate professor, pediatric critical care, infectious diseases physician21,  Reem A Mustafa, associate professor, nephrologist122,  John D Neary, methodologist, internist3,  Anila Qasim, research associate1,  Gabriel Rada, methodologist2324,  Irbaz Bin Riaz, methodologist, internist25,  Behnam Sadeghirad, assistant professor113,  Nigar Sekercioglu, assistant professor1,  Lulu Sheng, methodologist910,  Charlotte Switzer, methodologist1,  Britta Tendal, methodologist26,
Lehana Thabane, professor1,  George Tomlinson, senior biostatistician27,  Tari Turner, senior research fellow26,  Per O Vandvik, methodologist, internist14,  Robin WM Vernooij, methodologist2829,  Andrés Viteri-García, methodologist2330,  Ying Wang, methodologist, pharmacist1,  Liang Yao, methodologist1,  Zhikang Ye, methodologist, pharmacist1,  Gordon H Guyatt, methodologist, internist16,  Romina Brignardello-Petersen, methodologist1

Correspondence to: R Siemieniuk reed.siemieniuk@medportal.ca

Accepted 23 July 2020

 

Abstract

Objective 

To compare the effects of treatments for coronavirus disease 2019 (covid-19).

Design 

Living systematic review and network meta-analysis.

Data sources 

US Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.

Study selection 

Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.

Methods 

After duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.

Results 

23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.

Conclusion 

Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.

Systematic review registration 

This review was not registered. The protocol is included as a supplement.

Readers’ note 

This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Remdesivir; Chloroquine; Lopinavir; Corticosteroids.

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