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Practice Rapid Recommendations

A living WHO guideline on drugs to prevent covid-19

BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n526 (Published 02 March 2021) Cite this as: BMJ 2021;372:n526
Visual summary of recommendation Last updated 24 Mar 2023
Interventions Population This recommendation applies only to people with these characteristics: People who do not have covid-19 Hydroxychloroquine Recommendation against (strong) Tixagevimab-cilgavimab Recommendation against (conditional)

Hydroxychloroquine

Recommendation 1No interventionHydroxychloroquineorPeople who do not havecovid-19We recommend not usinghydroxychloroquine to prevent covid-19StrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Favours no interventionFavours hydroxychloroquineNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Evidence qualityEvents per 1000 people

Mortality No important difference33HighMore

Based on data from 6822 patients in 7 studiesHydroxychloroquine has little or noeffect on mortalityHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Admission to hospital No important difference31HighMore

Based on data from 7432 patients in 10 studiesHydroxychloroquine has little or noeffect on hospital admissionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Lab confirmed SARS-CoV-2 No important difference6259HighMore

Based on data from 8379 patients in 12 studiesHydroxychloroquine has little or noeffect on laboratory confirmedSARS-CoV-2 infectionHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Adverse events6 fewer2228HighMore

Based on data from 6153 patients in 9 studiesHydroxychloroquine has a smallincrease in adverse effects leading todiscontinuationHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect
See all outcomes

Individual considerations

The panel inferred that almost all well informed patients would not want to receive hydroxychloroquine given there are probably no positive effects and there was a risk of adverse events. The panel did not expect there would be much variation in values and preferences between patients for this intervention Values and preferences

Tixagevimab-cilgavimab

Recommendation 1No interventionTixagevimab-cilgavimaborPeople who do not havecovid-19We suggest not using tixagevimab-cilgavimab to prevent covid-19StrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Individual considerations

The panel reviewed in vitro evidence reducing the applicability of available trial data; while prophylactic use demonstrated modest reduction in laboratory-confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete Justification Conditions for use of treatment The panel inferred that, in the absence of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 sublineages, the majority of informed individuals would not choose to receive tixagevimab-cilgavimab Values and preferences Any prophylactic use of this intervention should be restricted to extremely vulnerable individuals, and patients presenting a sublineage that is neutralised in-vitro Typical characteristics of extremely vulnerable individuals include: People highly unlikely to mount an immune response following covid-19 vaccination People at increased risk of developing severe manifestations of covid-19 because of limited physiological reserve

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Linked Research

Prophylaxis against covid-19
  1. François Lamontagne, methods chair, critical care physician1,
  2. Miriam Stegemann, clinical chair, tixagevimab-cilgavimab, infectious disease physician2,
  3. Arnav Agarwal, internist3,
  4. Thomas Agoritsas, internist, methodologist456*,
  5. Reed Siemieniuk, internist, methodologist57*,
  6. Bram Rochwerg, critical care physician57*,
  7. Jessica Bartoszko, methodologist5*,
  8. Lisa Askie, methodologist8*,
  9. Helen Macdonald, UK research editor9*,
  10. Muna Al-Maslamani, medical doctor10,
  11. Wagdy Amin, chest physician11,
  12. Andre Ricardo Araujo Da Silva, paediatrician12,
  13. Fabian Alberto Jaimes Barragan, critical care physician13,
  14. Frederique Jacquerioz Bausch, infectious disease physician14,
  15. Erlina Burhan, chest physician15,
  16. Maurizio Cecconi, critical care physician16,
  17. Binila Chacko, critical care physician17,
  18. Duncan Chanda, infectious disease physician18,
  19. Vu Quoc Dat, infectious disease physician19,
  20. Bin Du, critical care physician20,
  21. Heike Geduld, emergency physician21,
  22. Patrick Gee, patient partner22,
  23. Muhammad Haider, respiratory physician23,
  24. Nerina Harley, intensive care physician24,
  25. Madiha Hashimi, critical care physician25,
  26. Fyezah Jehan, paediatrician26,
  27. David Hui, infectious disease physician27,
  28. Beverley J Hunt, rheumatology and haematology specialist28,
  29. Mohamed Ismail, respiratory physician29,
  30. Sushil Kabra, paediatric chest physician30,
  31. Seema Kanda, patient partner31,
  32. Leticia Kawano-Dourado, respiratory medicine physician32,
  33. Yae-Jean Kim, paediatric infectious disease physician33,
  34. Niranjan Kissoon, paediatric critical care physician34,
  35. Sanjeev Krishna, medical doctor35,
  36. Arthur Kwizera, critical care physician36,
  37. Thiago Lisboa, critical care physician37,
  38. Yee-Sin Leo, infectious disease specialist38,
  39. Imelda Mahaka, patient partner39,
  40. Manai Hela, emergency physician40,
  41. Giovanni Battista Migliori, respiratory physician41,
  42. Greta Mino, paediatric infectious disease physician42,
  43. Emmanuel Nsutebu, infectious disease physician43,
  44. Natalia Pshenichnaya, infectious disease physician44,
  45. Nida Qadir, critical care physician45,
  46. Shalini Sri Ranganathan, paediatric physician46,
  47. Saniya Sabzwari, geriatrician26,
  48. Rohit Sarin, chest physician47,
  49. Manu Shankar-Hari, critical care physician48,
  50. Michael Sharland, infectious disease physician49,
  51. Yinzhong Shen, infectious disease physician50,
  52. Joao Paulo Souza, obstetrics and gynaecology physician51,
  53. Tshokey Tshokey52,
  54. Sebastian Ugarte, intensive care physician53,
  55. Tim Uyeki, epidemiologist54,
  56. Sridhar Venkatapuram, ethicist48,
  57. Ablo Prudence Wachinou, respiratory physician55,
  58. Ananda Wijewickrama, infectious disease physician56,
  59. Dubula Vuyiseka, patient partner57,
  60. Jacobus Preller, intensive care physician, methodologist8*,
  61. Romina Brignardello-Petersen, methodologist5*,
  62. Elena Kum, MSc student5*,
  63. Anila Qasim, research associate5*,
  64. Dena Zeraatkar, methodologist5*,
  65. Andrew Owen, clinical pharmacologist58*,
  66. Gordon Guyatt, methodologist57*,
  67. Lyubov Lytvyn, methodologist5*,
  68. Michael Jacobs, clinical chair, hydroxychloroquine, infectious disease specialist59a,
  69. Per Olav Vandvik, methodologist, internist660*a,
  70. Janet Diaz, WHO lead, clinical team for covid-19 response8*a
  1. 1Université de Sherbrooke, Centre de recherche due CHU de Sherbrooke, Sherbrooke, Quebec, Canada
  2. 2Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, Berlin, Germany
  3. 3Division of General Internal Medicine, McMaster University, Hamilton, Ontario, Canada
  4. 4Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  5. 5Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  6. 6MAGIC Evidence Ecosystem Foundation, Oslo, Norway
  7. 7Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  8. 8World Health Organization, Geneva, Switzerland
  9. 9The BMJ, London, UK
  10. 10Communicable Disease Center, Qatar
  11. 11Ministry of Health and Population, Cairo, Egypt
  12. 12Departamento de Materno Infantil, Universidade Federal Fluminense, Brazil
  13. 13Antioquia University Medellín, Colombia
  14. 14Geneva University Hospital, Switzerland
  15. 15Infection Division, Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia
  16. 16Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
  17. 17Division of Critical Care Medicine at Christian Medical College, Vellore, India
  18. 18Adult Infectious Disease Centre, University Teaching Hospital, Lusaka, Zambia
  19. 19Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam
  20. 20Peking Union Medical College Hospital, Beijing, China
  21. 21Division of Emergency Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  22. 22USA
  23. 23Ministry of Health, Afghanistan
  24. 24Royal Melbourne Hospital, Melbourne, Australia
  25. 25Ziauddin University, Karachi, Pakistan
  26. 26Aga Khan University, Karachi, Pakistan
  27. 27Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong SAR, China
  28. 28Guy’s & St Thomas’ NHS Foundation Trust, London, UK
  29. 29Indira Gandhi Memorial Hospital, Maldives
  30. 30All India Institute of Medical Sciences, New Delhi, India
  31. 31McMaster University (alumnus)
  32. 32Pulmonary Division, Heart Institute (InCor)- HCFMUSP, Medical School, University of Sao Paulo, São Paulo, Brazil and Research Institute, Hospital do Coração (HCor), São Paulo, Brazil
  33. 33Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea
  34. 34Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada
  35. 35St George’s University of London, UK
  36. 36Department of Anaesthesia and Critical Care, College of Health Sciences, Makerere University, Kampala, Uganda
  37. 37Coraçao Hospital, São Paulo, Brazil
  38. 38National Center for Infectious Diseases, Singapore
  39. 39Pangaea Harare, Zimbabwe
  40. 40Emergency Medical Services, Faculty of Medicine, Tunis, Tunisia
  41. 41Pulmonology, Istituti Clinici Scientifii Maygeri, Italy
  42. 42Alcivar Hospital, Guayaquil, Ecuador
  43. 43Sheikh Shakhbout Medical City, Abu Dhabi, UAE
  44. 44Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
  45. 45Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
  46. 46University of Colombo, Colombo, Sri Lanka
  47. 47National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India
  48. 48King’s College, London, UK
  49. 49St. George’s University Hospital, London, UK
  50. 50Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
  51. 51University of Sao Paulo, Sao Paulo, Brazil
  52. 52JDW National Referral Hospital, Bhutan
  53. 53Faculty of Medicine Andres Bello University, Indisa Clinic, Santiago, Chile
  54. 54Influenza Division, Centers for Disease Control and Prevention, USA
  55. 55National Hospital for Tuberculosis and Pulmonary Diseases, Benin
  56. 56Ministry of Health, Sri Lanka
  57. 57University of Stellenbosch, South Africa
  58. 58University of Liverpool, Liverpool, UK
  59. 59Royal Free London NHS Foundation Trust, London, UK
  60. 60Department of Health Economics and Health Management, Institute for Health and Society, University of Oslo, Oslo, Norway
  61. *Not guideline development group member; resource for methodology, systematic review, and content support
  62. aco-senior author
  1. Correspondence to: Francois Lamontagne francois.lamontagne{at}usherbrooke.ca, or Miriam Stegemann miriam.stegemann{at}charite.de

Abstract

Clinical question What is the role of drugs in preventing covid-19?

Why does this matter?There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective.

Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19.

How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete.

Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.

Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Drugs could be used as prophylaxis to prevent covid-19 developing in those who are free from disease. Such drugs complement vaccines that, through developing immune responses to SARS-Cov-2, reduce the risk of developing covid-19 and its consequences. Drugs to prevent covid-19 could target whole populations, those at higher risk of becoming infected with SARS-CoV-2 (due to their work, social circumstances, or a particular exposure), or those at higher risk of death and poor outcomes if infected. As of 6 February 2023, there are 14 225 registered or ongoing trials investigating various drug interventions for covid-19 (see section on emerging evidence).1 This rapidly evolving evidence landscape requires trustworthy interpretation and expeditious clinical practice guidelines to inform clinicians, patients, governments, ministries, and health administrators.

This living guideline uses emerging evidence from randomised controlled trials (RCTs) on drugs to prevent covid-19 and complements the living WHO guideline on drugs to treat covid-19.2 The living network meta-analysis associated with this guideline incorporates new trial data and allows for analysis of comparative effectiveness.3 Details of the network meta-analysis and other related publications are listed in box 1. We also use additional relevant evidence on long term safety, prognosis, and patient values and preferences related to covid-19 treatments to inform the living guidance.

Box 1

Linked resources in this BMJ Rapid Recommendations cluster

RETURN TO TEXT

What triggered this version of the guideline?

The creation of a new recommendation on tixagevimab-cilgavimab prophylaxis followed the publication of one clinical trial suggesting potential benefits associated with the prophylactic use of these monoclonal antibodies and the subsequent emergence of in vitro evidence suggesting that these clinical trial data were potentially obsolete.4 For hydroxychloroquine, correspondence following the initial publication of the guideline justified re-examination of whether new evidence reinforced or contradicted the recommendation against hydroxychloroquine prophylaxis.5

How to use this guideline

This is a living guideline, so the recommendations included here will be updated, and new recommendations will be added for other prophylactic drugs for covid-19. The infographic provides a summary of the recommendations and includes links to MAGICapp for more details on the evidence and rationale for the recommendations. Box 2 outlines key methodological aspects of the guideline process.

Box 2

How this living guideline was created (see MAGICapp for full details https://app.magicapp.org/public/guideline/L6RxYL)

This guideline was developed by WHO and the MAGIC Evidence Ecosystem Foundation (MAGIC) with support from The BMJ. It was initiated due to an urgent need for trustworthy and living guidance to rapidly inform policy and practice worldwide during the covid-19 pandemic. WHO has partnered with MAGIC for their methodological support in the development and dissemination of living guidance for covid-19 drug treatments and prophylaxis, also published as BMJ Rapid Recommendations, to provide patients, clinicians, and policy makers with up to date, evidence based, and user-friendly guidelines.

Standards, methods, and processes for living and trustworthy guidance

The guideline development group (GDG) produced the recommendations following standards for trustworthy guideline development using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, in compliance with the WHO Handbook for Guideline Development 2nd Edition,6 the Institute of Medicine, and the Guideline International Network (G-I-N).7 Details are provided in the WHO guideline and MAGICapp (box 1).

Selection and support of the GDG

The methods chair (methodological expertise) and a clinical chair (content expertise) guided GDG discussions. Panel members were invited by WHO with the aim of achieving gender, geography, expertise, and patient representation balance in the GDG. No relevant conflict of interest was identified for any of the 34 GDG members.

The pre-selected clinical expert GDG, including patient partners, was convened most recently on 16 December 2022 to discuss methodological concepts relevant to guidelines for prophylactic interventions, review evidence summaries pertaining to hydroxychloroquine and tixagevimab-cilgavimab, and develop recommendations.

As recommended by the WHO handbook, the GDG aimed to create recommendations based on consensus but elected, at the beginning of the first GDG meeting, to call a vote if a consensus could not be reached. Before discussions started, the GDG determined that a simple majority would provide the direction of the recommendation and that 80% would be required to make a strong recommendation.

Guideline perspective, outcomes, and values and preferences

The target audience for this guidance consists primarily of clinicians and healthcare decision makers. The GDG considered an individual patient perspective but also took account of contextual factors (such as resources, feasibility, acceptability, equity) to accommodate a global context and the realities of different countries and healthcare systems.

In the absence of empirical evidence on values and preferences guiding decisions for covid-19 prophylactic interventions, the GDG members relied on their own judgments of how well-informed individuals would value benefits, harms, and burdens of prophylactic interventions. The GDG concluded that:

  • Mortality would be the outcome most important to individuals, followed by need for hospital admission, laboratory confirmed SARS-CoV-2 infection, and adverse effects leading to discontinuation.

  • Most patients would be reluctant to use an intervention for which the evidence left high uncertainty regarding effects on outcomes they consider important, or when evidence suggested a low certainty of benefit. When beneficial effects, if present, would be very small, almost all patients would decline to use such an intervention.

  • The GDG also considered optimal resource use at a public health level. The GDG placed a low value on allocating substantial resources for uncertain benefit and, conversely, a high value on preserving resources for interventions with a high certainty of benefit.

The GDG acknowledged, however, that values and preferences could vary. There may be individuals inclined to use a prophylactic intervention when an important benefit cannot be ruled out, particularly when the underlying condition is potentially fatal. On the other hand, other individuals will have a high threshold of likely benefit before opting to take medications if they are not yet ill. Although the GDG focused on an individual patient perspective, the members also considered a population perspective in which feasibility, acceptability, equity, and cost are important considerations, particularly when a very large number of otherwise healthy individuals might need to be treated before preventing one outcome.

Sources of evidence

To create recommendations, the GDG relied on evidence synthesised in a living network meta-analysis, as requested by the GDG.3 While the investigators responsible for the meta-analyses rated the certainty of the evidence, this was re-assessed independently by the GDG.

Derivation of absolute effects for drug treatments

The baseline risks were calculated from data from the control groups of trials included in the network meta-analysis, which also yielded the estimate of relative effects of prophylactic interventions.1 The evidence summaries that informed the guideline recommendation reported the anticipated absolute effects of hydroxychloroquine and tixagevimab-cilgavimab compared with usual care across all patient-important outcomes, with explicit judgments of certainty in the evidence for each outcome. For mortality, the event rate among all participants randomised to standard care or placebo was used to calculate the baseline risk. For all other outcomes, the median event rate in the standard care or placebo arms was used, with each study weighted equally.

Special considerations for recommendations on prophylaxis

As detailed in the full WHO guideline (see box 1), the GDG considered the implications of very low risks of critical outcomes such as death in trials of prophylactic interventions. The GDG opted to consider the magnitude of effect (for example, trivial, small, moderate, or large effect) when rating certainty.

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Who do the recommendations apply to?

This guideline applies to all individuals who do not have covid-19. For hydroxychloroquine, the GDG ultimately concluded that this recommendation was applicable irrespective of known exposure to individuals with SARS-CoV-2 infection or of different drug doses, based on pre-specified subgroup analyses as further outlined below.

In the case of tixagevimab-cilgavimab, the GDG concluded that prophylactic use of tixagevimab-cilgavimab should be strictly restricted to situations where there could be high certainty that the circulating sub-lineages exhibit in vitro neutralisation activity equivalent to those circulating in populations and regions when and where the supporting clinical trial was conducted. This decision was based on in vitro evidence suggesting lack of neutralisation efficacy for new circulating Omicron sub-lineages, and it applies to all individuals who do not have covid-19. The conditional recommendation acknowledges that a minority of high risk patients who have not been vaccinated or who are severely immunocompromised may choose to receive tixagevimab-cilgavimab. This exception would apply only where it could be established that such high risk patients were at risk of becoming infected with the SARS-CoV-2 sub-lineages that were prevalent during the trial.

The guidance

Hydroxychloroquine

Hydroxychloroquine is an immunomodulator that blocks toll-like receptors reducing dendritic cell activation. It is used to treat rheumatoid arthritis and systemic lupus erythematosus. It has an antiviral effect against many viruses in vitro, including SARS-CoV-2, but a clinically useful antiviral effect has not been shown for any viral infection.

The recommendation was informed by the linked systematic review and network meta-analysis that included 12 trials (8379 participants) randomising participants to hydroxychloroquine or to standard care/placebo.8910111213141516171819 The trials included participants from North and South America and Europe who either had a known exposure to a person with SARS-CoV-2 infection or who were considered at risk given their professional occupations (such as healthcare workers). The most recent LNMA publication contains an additional trial comparing hydroxychloroquine to active interventions.320

Recommendation: We recommend against the use of hydroxychloroquine as prophylaxis in individuals who do not have covid-19 (strong recommendation).

Understanding the recommendation

Balance of benefits and harm—Used prophylactically, hydroxychloroquine has no or little effect on death and hospital admission (high certainty) and has no or little effect on laboratory confirmed SARS-CoV-2 infection (high certainty). It increases the risk of adverse effects leading to discontinuation of the drug (high certainty).

Subgroup effects—There were no subgroup effects according to known exposure to a person with SARS-CoV-2 infection or hydroxychloroquine dose regimen; extremely low event rates precluded investigation of subgroup effects for mortality. In the absence of subgroup effects, the GDG assumed similar relative effects across subgroups. As no subgroup effect modification was found, the strong recommendation is applicable across risk groups and dose regimens of hydroxychloroquine. Certain subgroups of vulnerable individuals, such as immunocompromised patients, were under-represented in previous hydroxychloroquine prophylaxis trials. However, the GDG maintained its view that, given the existing evidence, it would be extremely unlikely that large number of under-represented individuals would consent to participate in future hydroxychloroquine trials, and that these would find that hydroxychloroquine prophylaxis meaningfully reduces mortality reduction even in those subgroups.

Values and preferences—Applying the established values and preferences (box 2), the GDG inferred that almost all well-informed patients would decline hydroxychloroquine.

Applicability—Regarding special populations, none of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, as for other under-represented subgroups, the GDG had no reason to think that children would respond any differently to prophylactic hydroxychloroquine. There were similar considerations with regards to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently to other adults. Hydroxychloroquine crosses the placental barrier, and there are concerns that it may lead to retinal damage in neonates.

Resource implications, feasibility, equity, and human rights—Hydroxychloroquine is relatively inexpensive and is widely available, including in low resource settings. Although the cost may be low per patient, the overall cost of delivering a prophylactic intervention on a large scale may be substantial. Moreover, the GDG raised concerns about diverting hydroxychloroquine stocks away from patients with other conditions for whom this medication is indicated.21

Uncertainties—The GDG acknowledged that a strong recommendation against hydroxychloroquine to prevent covid-19 indicates that this area is no longer a research priority and that resources devoted to clinical research should rather be oriented to evaluate more promising prophylactic interventions. The GDG felt that further research was unlikely to be acceptable to under-represented subgroups or that it would uncover a subgroup of patients who would benefit from hydroxychloroquine prophylaxis on the most important outcomes (mortality, admission to hospital, and laboratory confirmed SARS-CoV-2 infection).

Tixagevimab-cilgavimab

Tixagevimab and cilgavimab are a combination (Evusheld, AZD7442) of human monoclonal antibodies that bind to non-overlapping regions for the receptor-binding domain of the SARS-CoV-2 Spike protein. Tixagevimab-cilgavimab is administered as a single intramuscular dose of 300 mg.22

The combination of tixagevimab and cilgavimab administered prophylactically as intravenous infusion prevented infection in animal models by ancestral SARS-CoV-2, leading to further interest in its use for this indication in clinical practice. However, animal data for currently circulating variants are unavailable, and evidence from in vitro neutralisation studies shows that for more recent variants (including BA.2.75.2, BQ.1, BQ.1.1, and XBB lineages) the in vitro neutralisation of both antibodies is compromised. The GDG concluded that this in vitro evidence rendered the clinical trial results obsolete.

Recommendation: We suggest not to use tixagevimab-cilgavimab in individuals who do not have covid-19 (conditional recommendation).

Understanding the recommendation—When moving from the evidence to the conditional recommendation against the use of tixagevimab-cilgavimab to prevent covid-19-related outcomes, the GDG emphasised in vitro evidence reducing the applicability of trial data. While clinical trial results suggested prophylactic use of tixagevimab-cilgavimab reduced the occurrence of laboratory confirmed covid-19, the GDG concluded that these modest benefits represented the best-case scenario obtained under lineages of SARS-CoV-2 that have since been replaced. Having concluded that recently emerged in vitro evidence rendered the clinical trial results obsolete, the GDG abstained from rating the certainty of the underlying evidence. A conditional recommendation was made recognising that, while it was extremely unlikely for previous SARS-CoV-2 sub-lineages to re-emerge, it nonetheless remained theoretically possible that former sub-lineages would continue to cause covid-19 in certain regions, and that, assuming that real-time monitoring of the prevalence of SARS-CoV-2 sub-lineages was available, a significant number of extremely vulnerable individuals may choose to receive prophylactic tixagevimab-cilgavimab. The GDG also considered that, although in vitro neutralisation is required for tixagevimab-cilgavimab to be considered for use as prophylaxis, it does not guarantee clinical effectiveness.

Applicability—While the recommendation applies to all individuals who do not have covid-19, a conditional recommendation implies that a minority may opt to receive this prophylactic intervention. Should this situation arise, all GDG members agreed that any prophylactic use of this intervention should be limited to a minority of patients who may be extremely vulnerable, in settings where prevailing SARS-CoV-2 sub-lineages were the same as the ones that caused covid-19 during the trial. Such patients include those who are highly unlikely to mount an immune response after covid-19 vaccination and who, due to a limited physiological reserve, are at high risk of developing severe manifestations of covid-19.

Balance of benefits and harms—See MAGICapp for a summary of findings from clinical trial data; this data ultimately did not directly bear on the recommendation because it was considered obsolete.

Values and preferences—The GDG inferred that, in the absence of compelling evidence of clinical effectiveness for the currently circulating SARS-CoV-2 sub-lineages, most informed individuals would not choose to receive tixagevimab-cilgavimab.

Resource implications, feasibility, equity, and human rights—The GDG placed a low value on potential benefits in regions where circulating SARS-CoV-2 sub-lineages demonstrate neutralisation activity, and considered that tixagevimab-cilgavimab is a costly intervention of limited availability and requiring parenteral administration. Conversely, the GDG placed a high value on preserving resources for interventions with a high certainty of benefit and noted the availability of effective therapeutic options for patients with covid-19.

Uncertainties—All members of the GDG acknowledged that the available in vitro data suggests that the results of the published clinical trials are now, at best, highly uncertain. However, the GDG was split regarding the strength of recommendation. This was driven by the certainty with which guideline users could rule out that the prevailing SARS-CoV-2 sub-lineages in their region would be resistant to tixagevimab-cilgavimab neutralisation. Those 14 panelists who voted for a strong recommendation pointed out that emerging sub-lineages tended to rapidly replace older sub-lineages all over the globe and that regional real-time monitoring of circulating SARS-CoV-2 sub-lineages was onerous and unrealistic in most geographical areas. Notwithstanding, those 17 panelists who voted for a conditional recommendation argued that, provided that these conditions could be satisfied, some highly vulnerable patients may choose to receive tixagevimab-cilgavimab.

The GDG inferred that restricting use of tixagevimab-cilgavimab to clinical trials would be futile considering the large number of participants required to demonstrate clinical effectiveness.

Emerging evidence

The unprecedented volume of planned and ongoing studies for covid-19 interventions implies that further evidence will emerge to inform policy and practice.1 An overview of registered and ongoing trials for covid-19 therapeutics and prophylaxis is available from the Infectious Diseases Data Observatory (through their living systematic review of covid-19 clinical trial registrations1), the WHO website, and other repositories such as the COVID-NMA initiative.

How patients were involved in the creation of this article

The guideline development GDG initially included four patient-partners who have had covid-19; with one taking active part in this update. Their perspectives were crucial in deciding on clinical questions and considering the values and preferences associated with drugs to prevent covid-19.

Acknowledgments

We thank all the following collaborators who contributed to this endeavour, as detailed in the WHO guidance (see link in box 1)

• World Health Organisation (WHO) Secretariat for Therapeutics and COVID-19

• External reviewers for WHO

We also thank

• The living systematic review and network meta-analysis team, led by investigators Reed Siemienuk and Romina Brignardello-Petersen at McMaster University, Canada

• BMJ editorial team with Tom Nolan (head of education), Will Stahl-Timmins (data graphics designer) and Greg Cotton (technical editor) of this living guideline publication in The BMJ

• Alistair MacLean, Brittany Maguire, Philippe Guerin, and Sumayyah Rashan for providing an overview of registered and ongoing trials, from the Infectious Diseases Data Observatory (IDDO) living systematic review for covid-19 clinical trial registration (https://www.iddo.org/research-themes/covid-19/live-systematic-clinical-trial-review).

• Andrew Owen (University of Liverpool, UK) for contributions on pharmacological considerations and analyses

Footnotes

  • Funding: Bill & Melinda Gates Foundation, UNITAID, 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 guideline 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 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 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 was managed by WHO, and internal review at The BMJ. Post-publication review through rapid responses on bmj.com and through MAGICapp.

This article is made freely available for personal use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://bmj.com/coronavirus/usage

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