World

Therapeutics and COVID-19 (Living Guidelines, 24 September 2021)

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Manual and Guideline
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1. Summary: what is this living guideline?

Clinical question: What is the role of drugs in the treatment of patients with COVID-19?

Target audience: The target audience is clinicians and health care decision-makers.

Current practice: The evidence base for therapeutics for COVID-19 is increasing rapidly, and some treatments of proven benefit have emerged. Numerous randomized trials of many drugs are underway to further inform practice. This version of the WHO living guideline contains new recommendations on a combination of neutralizing monoclonal antibodies (casirivimab and imdevimab) based on four randomized controlled trials (RCTs).

Recommendations: In this update, the panel makes a conditional recommendation to use casirivimab and imdevimab in non-severe patients, the condition being patients’ risk of severe disease: patients at highest risk represent good candidates for use of the intervention. The panel also makes a conditional recommendation to use casirivimab and imdevimab in patients with severe and critical infection, the condition being seronegative status.

Previous recommendations include:

  • a strong recommendation for systemic corticosteroids in patients with severe and critical COVID-19;

  • a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab) in patients with severe and critical COVID-19;

  • a conditional recommendation against systemic corticosteroids in patients with non-severe COVID-19;

  • a conditional recommendation against remdesivir in hospitalized patients with COVID-19;

  • a strong recommendation against hydroxychloroquine in patients with COVID-19 of any severity;

  • a strong recommendation against lopinavir/ritonavir in patients with COVID-19 of any severity;

  • a recommendation against ivermectin in patients with COVID-19 of any severity, except in the context of a clinical trial.

How this guideline was created: A Guideline Development Group (GDG) of content experts, clinicians, patients, ethicists, and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. No conflict of interest was identified for any panel member or other contributors to the guideline development process. This living guideline represents an innovation from the World Health Organization (WHO), driven by the urgent need for global collaboration to provide trustworthy and evolving COVID-19 guidance informing policy and practice worldwide. WHO has partnered with the non-profit MAGIC Evidence Ecosystem Foundation (MAGIC) for methodologic support and development, and dissemination of living guidance for COVID-19 drugs to prevent and treat COVID-19. These guidelines are also published in the BMJ, supported by a living systematic review with network meta-analysis (LNMA) that informs the recommendations.

The latest evidence: The GDG's recommendations for casirivimab and imdevimab were informed by results from the LNMA that pooled data from four RCTs with 4722 patients with non-severe disease, and one RCT (RECOVERY) with 9785 patients with severe or critical disease that included a crucial subgroup analysis examining effect modification associated with serological status (seropositive versus seronegative).

In non-severe patients, the pooled data from 3432 patients in two RCTs showed, because of very low baseline risk, trivial or no effects of the intervention on mortality or need for mechanical ventilation (moderate certainty evidence). In 4722 non-severe patients in four RCTs, casirivimab and imdevimab likely reduce need for hospitalization (moderate certainty evidence; odds ratio [OR] 0.29; 95% confidence interval [CI]: 0.17–0.48; absolute effect estimate using the baseline risk in the trials of 29 fewer hospitalizations per 1000 patients; 95% CI: 35 fewer to 21 fewer). The absolute benefit will be appreciably greater in those at highest risk for hospitalization and much lower for those at low risk (the majority of the population with non-severe illness).

In the overall population of patients with severe and critical COVID-19, casirivimab and imdevimab may not have an impact on mortality (low certainty evidence; OR 0.94; 95% CI: 0.86–1.03; absolute effect estimate 8 fewer per 1000 patients; 95% CI: 18 fewer to 4 more). Evidence was of low certainty because of imprecision and high likelihood that casirivimab and imdevimab have, in the seronegative and seropositive patients included in the overall group, very different effects. In this population the evidence regarding the impact of the intervention on need for mechanical ventilation and duration of hospitalization was very low certainty.

A credible subgroup effect demonstrates that casirivimab and imdevimab likely reduce mortality in patients who are seronegative (moderate certainty evidence; RR 0.85; 95% CI: 0.76–0.95; for severe patients absolute effect estimate 39 fewer per 1000; 95% CI: 62 fewer to 13 fewer; for critical patients absolute effect estimate 69 fewer per 1000; 95% CI: 110 fewer to 23 fewer). In the seronegative patients, the intervention possibly reduces the need for mechanical ventilation (moderate certainty evidence; RR 0.87; 95% CI: 0.77–0.98; absolute effect estimate 42 fewer per 1000; 95% CI: 74 fewer to 6 fewer). Aside from the credible subgroup effect, the GDG found no evidence of subgroup effects on age or time from onset of illness in the non-severe, or on age, time from onset of illness, and severity in the severe and critically ill.

Understanding the recommendations: When moving from evidence to recommendations to use casirivimab and imdevimab in non-severe patients, the GDG recognized the limited availability, in relation to the number of eligible patients, of casirivimab and imdevimab and the very small benefits in reducing hospitalization that low-risk patients would achieve with use of the intervention. Thus the conditional recommendation reflects the GDG’s view that drug administration be reserved for those at high risk. Although there is no established decision tool to definitively identify those at high risk of hospitalization, evidence exists that factors substantially increasing risk include no prior vaccination, older age, immunosuppression, and presence of chronic conditions.

In patients with severe or critical illness, the conditional recommendation in favour of casirivimab and imdevimab use reflects the likelihood that any benefits are restricted to patients who are seronegative. This implies rapid identification of serological status at the time of presentation of severe or critical illness to guide use in this population. Several rapid, relatively inexpensive tests are available with adequate performance characteristics that could be used to identify patients who are seronegative and likely to benefit from casirivimab and imdevimab administration.

Info Box

This WHO Therapeutics and COVID-19: living guideline now includes two recommendations regarding the combination of neutralizing monoclonal antibodies, casirivimab and imdevimab: a conditional recommendation in favour of use in non-severe patients (the condition being patients’ risk of severe disease: patients at highest risk represent good candidates for use of the intervention); and a conditional recommendation in favour of use in the severe and critically ill (the condition being seronegative status).

The section text provides an executive summary of the guidance. The first version of the living WHO guideline, published 2 September 2020, provides recommendations for corticosteroids; the second version, published 20 November 2020, provides recommendations on remdesivir; the third version, published 17 December 2020, provides recommendations on hydroxychloroquine and lopinavir/ritonavir; the fourth version, published 31 March 2021, provides recommendations on ivermectin; and the fifth version, published 6 July 2021, provides recommendations on IL-6 receptor blockers. This update does not include changes to the recommendations for any of these other drugs.

This living guideline will incorporate new recommendations on other therapies for COVID-19 and updates on existing recommendations. The guideline is therefore written, disseminated, and updated in MAGICapp, with a user-friendly format and easy to navigate structure that accommodates dynamically updated evidence and recommendations, focusing on what is new while keeping existing recommendations within the guideline.

Please visit the WHO website for the latest version of the guidance, also available in the BMJ as Rapid Recommendations, together with the living network meta-analysis (LNMA), a major evidence source for the guidelines.

Guidelines with recommendations on prophylaxis against COVID-19 have been published separately, and the WHO COVID-19 Clinical management: living guidance can also be found separately.