A living WHO guideline on drugs for covid-19

UPDATES: This is the eighth version (seventh update) of a living guideline. It replaces earlier versions (4 September 2020, 20 November 2020, 17 December 2020, 31 March 2021, 6 July 2021, 23 September 2021, and 6 December 2021). The previous versions can be found 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 increasing with numerous recently completed randomised controlled trials (RCTs). This update adds new recommendations on Janus kinase (JAK) inhibitors based on three RCTs with 2659 participants for baricitinib, two RCTs with 475 participants for ruxolitinib, and one RCT with 289 participants for tofacitinib. It also adds a recommendation for sotrovimab (monoclonal antibody) based on one RCT with 1057 participants, that was completed before the emergence of the omicron variant.

NEW RECOMMENDATION: The Guideline Development Group (GDG) made: • A strong recommendation for the use of baricitinib as an alternative to interleukin-6 (IL-6) receptor blockers, in combination with corticosteroids, in patients with severe or critical covid-19 • A conditional recommendation against the use of ruxolitinib and tofacitinib for patients with severe or critical covid-19 • A conditional recommendation for the use of sotrovimab in patients with non-severe covid-19, restricted to those at highest risk of hospitalisation. Following the publication of a previous conditional recommendation for casirivimab- imdevimab, pre-clinical evidence has emerged suggesting that this monoclonal antibody combination lacks neutralisation activity against the omicron variant in vitro. Sotrovimab has been reported to retain activity against omicron in pseudovirus assays but with higher concentrations being required for neutralisation. More data are required to ascertain whether efficacy against the omicron variant will be maintained at the studied doses of monoclonal antibodies, and these living guidelines will be updated when additional data becomes available.

UNDERSTANDING THE NEW RECOMMENDATIONS: When moving from evidence to recommendations, the GDG considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. The strong recommendation for baricitinib in those with severe or critical illness reflects moderate certainty evidence for benefits on mortality, duration of mechanical ventilation, and hospital length of stay, with no observed increase in adverse events leading to drug discontinuation. Baricitinib and IL-6 receptor blockers have similar effects; when both are available, choose one based on issues including cost and clinician experience. The conditional recommendation against the use of ruxolitinib and tofacitinib was driven by low certainty evidence from small trials, failing to demonstrate benefit, and suggesting a possible increase in serious adverse events for tofacitinib. A conditional recommendation for the monoclonal antibody sotrovimab in patients with non-severe illness reflects substantial reduction in risk of hospitalisation in those at higher risk, and trivial benefits in those at lower risk. There were insufficient data to recommend one monoclonal antibody treatment over another, and evidence on their efficacy for emerging variants is likely to influence future recommendations.

PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19—a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab); and a conditional recommendation for casirivimab-imdevimab, for those having seronegative status. • Recommended for patients with non-severe covid-19—a conditional recommendation for casirivimab-imdevimab, for those at highest risk of severe illness. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma, except in the context of a clinical trial. • Not recommended, regardless of covid-19 illness severity—a conditional recommendation against remdesivir; a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial.

ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates three new recommendations on two therapies for covid-19, and updates existing recommendations. The GDG typically evaluates a therapy when 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. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations.