A living WHO guideline on drugs for covid-19
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3379 (Published 04 September 2020) Cite this as: BMJ 2020;370:m3379©BMJ Publishing Group Limited.
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- Arnav Agarwal, methodologist, internist123*,
- Beverley J Hunt, clinical chair ivermectin update, remdesivir update, molnpuiravir update, nirmatrelvir-ritonavir update, VV116 update, indirect comparisons for non-severe illness, haematologist4,
- Miriam Stegemann, clinical chair fluvoxamine, colchicine, baricitinib update, sotrovimab update, nirmatrelvir/ritonavir update, casirivimab-imdevimab update, infectious disease and chest physician5,
- Bram Rochwerg, methods chair molnupiravir, convalescent plasma, IL-6 receptor blockers, ivermectin, remdesivir,lopinavir-ritonavir, remdesivir update, molnupiravir update, nirmatrelvir-ritonavir update and VV116 update, critical care physician12*,
- François Lamontagne, methods chair corticosteroids, sotrovimab, fluvoxamine, colchicine, baricitinib update, sotrovimab update, casirivimab-imdevimab update and nirmatrelvir/ritonavir update, critical care physician6*,
- Reed AC Siemieniuk, methods chair hydroxychloroquine12*,
- Thomas Agoritsas, internist, methodologist137*,
- Lisa Askie, WHO staff, clinical team for covid-19 response8*,
- Lyubov Lytvyn, methodologist1*,
- Yee-Sin Leo, clinical chair corticosteroids, infectious disease specialist9,
- Helen Macdonald, UK research editor10*,
- Linan Zeng, methodologist1*,
- Ahmed Alhadyan11,
- Al-Maslamani Muna, medical doctor12,
- Wagdy Amin, chest physician13,
- André Ricardo Araujo da Silva, pediatrician14,
- Diptesh Aryal, intensivist15,
- Fabian A Jaimes Barragan, internist16,
- Frederique J Bausch, internist17,
- Erlina Burhan, chest physician, infectious disease physician18,
- Carolyn S Calfee, intensive care physician19,
- Maurizio Cecconi, critical care physician20,
- Binila Chacko, intensive care physician21,
- Duncan Chanda, infectious disease physician22,
- Vu Quoc Dat, infectious disease physician23,
- An De Sutter, public health and primary care physician24,
- Bin Du, critical care physician25,
- Stephen Freedman, pediatrician26,
- Heike Geduld, clinical chair remdesivir update, emergency physician27,
- Patrick Gee, patient partner28,
- Muhammad Haider, respiratory medicine physician,29,
- Matthias Gotte, medical microbiology and immunology physician30,
- Nerina Harley, critical care physician31,
- Madiha Hashmi, critical care physician32,
- David Hui33,
- Mohamed Ismail34,
- Fyezah Jehan, paediatric infectious disease and maternal health physician34,
- Sushil K Kabra, paediatric chest physician35,
- Seema Kanda, patient partner36,
- Yae-Jean Kim, paediatric infectious disease physician37,
- Niranjan Kissoo, paediatric critical care physician38,
- Sanjeev Krishna, molecular parasitology physician39,
- Krutika Kuppalli, WHO staff, clinical team for covid-19 response8,
- Arthur Kwizera, critical care physician40,
- Marta Lado Castro-Rial, WHO staff, clinical team for covid-19 response8*,
- Thiago Lisboa, critical care physician41,
- Rakesh Lodha, paediatrician42,
- Imelda Mahaka, patient partner43,
- Hela Manai, emergency physician44,
- Marc Mendelson, infectious disease physician45,
- Giovanni Battista Migliori, respiratory medicine physician46,
- Greta Mino, paediatric infectious disease physician47,
- Emmanuel Nsutebu, infectious disease physician48,
- Jessica Peter, patient partner49,
- Jacobus Preller, WHO staff, clinical team for covid-19 response8*,
- Natalia Pshenichnaya, infectious disease physician50,
- Nida Qadir, critical care physician51,
- Shalini S Ranganathan, paediatric physician52,
- Pryanka Relan, WHO staff, clinical team for covid-19 response8*,
- Jamie Rylance, WHO staff, clinical team for covid-19 response8*,
- Saniya Sabzwari, geriatrician53,
- Rohit Sarin, chest physician54,
- Manu Shankar-Hari, critical care physician5,
- Michael Sharland, infectious disease physician55,
- Yinzhong Shen, infectious disease physician56,
- Joao P Souza, obstetrics and gynaecology physician57,
- Ronald Swanstrom, infectious disease researcher58,
- Tshokey Tshokey, microbiologist59,
- Sebastian Ugarte, intensive care physician60,
- Timothy Uyeki, respiratory medicine physician61,
- Evangelina Vazquez Curiel, patient partner62,
- Sridhar Venkatapuram, ethicist63,
- Dubula Vuyiseka, patient partner64,
- Ananda Wijewickrama, infectious disease physician65,
- Lien Tran, methodologist60*,
- Dena Zeraatkar, methodologist1*,
- Jessica J Bartoszko, methodologist1*,
- Long Ge, methodologist161*,
- Romina Brignardello-Petersen, methodologist1*,
- Andrew Owen, clinical pharmacologist62*,
- Gordon Guyatt, methods chair casirivimab-imdevimab, janus kinase inhibitors, nirmatrelvir/ritonavir, ivermectin update, remdesivir update and indirect comparisons for non-severe illness, methodologist12a*,
- Janet Diaz, WHO lead, clinical team for covid-19 response6a*,
- Leticia Kawano-Dourado, clinical chair molnupiravir, convalescent plasma and sotrovimab, respiratory medicine physician63,
- Michael Jacobs, clinical chair IL-6 receptor blockers, ivermectin, remdesivir, hydroxychloroquine, lopinavir-ritonavir casirivimab-imdevimab, janus kinase inhibitors, nirmatrelvir/ritonavir, remdesivir and remdesivir update, infectious disease specialist64a,
- Per Olav Vandvik, methodologist, internist365a*
- 1Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- 2Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- 3MAGIC Evidence Ecosystem Foundation, Oslo, Norway
- 4King’s College London, St Thomas’ Hospital, London, UK
- 5National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
- 6Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Quebec, Canada
- 7Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
- 8World Health Organization, Geneva, Switzerland
- 9National Center for Infectious Diseases, Singapore
- 10The BMJ, London, UK
- 11Saudi Arabia
- 12Communicable Disease Center, Qatar
- 13Ministry of Health and Population, Cairo, Egypt
- 14Fluminense Federal University, Brazil
- 15Mediciti Hospital, Nepal
- 16Antioquia University Medellin, Colombia
- 17Geneva University Hospital, Switzerland
- 18Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas, Indonesia
- 19University of California, San Francisco, USA
- 20Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center, Italy
- 21Christian Medical College, Vellore, India
- 22Adult Infectious Disease Centre, University Teaching Hospital, Lusaka, Zambia
- 23Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam
- 24University of Gent, Belgium
- 25Peking Union Medical College Hospital, Beijing, China
- 26Department of Pediatrics, Cumming School of Medicine, University of Calgary, Canada
- 27Division of Emergency Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- 28United States
- 29Ministry of Health, Afghanistan
- 30University of Alberta, Canada
- 31Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia
- 32Ziauddin University, Karachi, Pakistan
- 33Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, China
- 34Indira Gandhi Memorial Hospital, Maldives
- 35Aga Khan University, Pakistan
- 36All India Institute of Medical Sciences, New Delhi, India
- 37McMaster University, Canada (alumnus)
- 38Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea
- 39Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada
- 40St George’s University of London, UK
- 41Department of Anaesthesia and Critical Care, College of Health Sciences, Makerere University, Kampala, Uganda
- 42HCOR Hospital do Coracao, Sao Paulo, Brazil
- 43Department of Paediatrics, All India Institute of Medical Sciences, India
- 44Zimbabwe
- 45Emergency Medical Services, Faculty of Medicine, Tunis, Tunisia
- 46Groote Schuur Hospital, University of Cape Town, South Africa
- 47Clinical Scientific Institutes Maugeri, Italy
- 48Alcivar Hospital in Guayaquil, Ecuador
- 49Sheikh Shakhbout Medical City, Abu Dhabi
- 50Malaysia
- 51Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
- 52Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- 53Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- 54Aga Khan University, Karachi, Pakistan
- 55Guy’s and St Thomas’ NHS Foundation Trust, London, UK
- 56St. George’s University Hospital, UK
- 57University of Colombo, Sri Lanka
- 58University of Sao Paulo, Brazil
- 59Charité - Universitätsmedizin Berlin, Germany
- 60University of North Carolina, USA
- 61JDW National Referral Hospital, Bhutan
- 62Faculty of Medicine Andres Bello University, Indisa Clinic, Santiago, Chile
- 63Influenza Division, U.S. Centers for Disease Control and Prevention, USA
- 64King’s College, London, UK
- 65Department of Medicine, Lovisenberg Diaconal Hospital Trust, Oslo, Norway
- *Not Guideline Development Group member; resource for methodology, systematic review, and content support
- aco-senior author
- Correspondence for this iteration to: Bram Rochwerg bram.rochwerg{at}gmail.com; Beverley Hunt beverley.hunt{at}gstt.nhs.uk; Miriam Stegemann miriam.stegemann{at}charite.de; Gordon Guyatt guyatt{at}mcmaster.ca
Abstract
Updates This is the fourteenth version (thirteenth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.
Clinical question What is the role of drugs in the treatment of patients with covid-19?
Context The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics.
What is new?The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19.
About this guideline This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.
Future recommendations Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.
Footnotes
Funding: Bill & Melinda Gates Foundation, Norwegian Directorate of Public Health and Germany provided funding for this guideline, with MAGIC providing pro-bono contributions and support to WHO in the context of the covid-19 pandemic.
Competing interests: All GDG members have completed the WHO interest disclosure form. All authors have completed the BMJ Rapid Recommendations interest of disclosure form. The WHO, MAGIC and The BMJ judged that no GDG member or co-chair had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the GDG to make fully informed decisions. MAGIC and TheBMJ assessed declared interests from other co-authors of this publication and found no relevant conflicts of interests.
Provenance and peer review: This publication was commissioned by The BMJ in partnership with WHO and the MAGIC Evidence Ecosystem Foundation, in the context of the BMJ Rapid Recommendations. Pre-publication internal and external peer-review managed by WHO, and internal review at The BMJ. Post-publication review through rapid responses on bmj.com and through MAGICapp.