This is the tenth version (ninth update) of the living guideline, replacing earlier versions, available as data supplements. New recommendations will be published as updates to this guideline.
What is the role of drugs in the treatment of patients with covid-19?
The evidence base for therapeutics for covid-19 is evolving with numerous recently completed randomised controlled trials (RCTs). In this update the Guideline Development Group (GDG) developed new recommendations for patients with non-severe covid-19, concerning the use of nirmatrelvir/ritonavir (2 RCTs, 3100 participants) and remdesivir (5 RCTs, 2710 participants). We have also revised the structure of the guideline to accommodate for an increasing number of effective treatment options to choose between.
New recommendations for patients with non-severe covid-19
• Nirmatrelvir/ritonavir: a strong recommendation for its use in patients at highest risk of hospitalisation; and a conditional recommendation against its use in patients at low risk of hospitalisation. In the absence of trial data, no recommendation on nirmatrelvir/ritonavir was made in patients with severe or critical illness.
• Remdesivir: a conditional recommendation for its use in patients at highest risk of hospitalisation.
Understanding the new recommendations
In patients with non-severe illness at highest risk of hospitalisation, the recommendations for treatment with nirmatrelvir/ritonavir and remdesivir reflect what the GDG considered to be important reductions in admission to hospital (moderate certainty) with little or no impact on mortality, mechanical ventilation, time to symptom resolution (low to very low certainty), and adverse effects leading to drug discontinuation (high certainty for nirmatrelvir/ritonavir, moderate certainty for remdesivir), though diarrhoea and altered taste were noted more often with nirmatrelvir/ritonavir.
Several treatment alternatives are now available for patients with non-severe covid-19 at highest risk of hospitalisation. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis have been used to inform the use of one drug over another with a related mechanism of action. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir), duration of treatment, and time from onset of symptoms to starting treatment in the trials.
The strong recommendation for nirmatrelvir/ritonavir reflects what the GDG considered to represent a superior choice over other treatment options for those with non-severe illness at highest risk; it may prevent more hospitalisations than the alternatives, has fewer harms than molnupiravir, and is easier to administer than intravenous options such as remdesivir and the monoclonal antibodies. For monoclonal antibodies, efficacy may depend on the given SARS-CoV-2 variant, with a less certain benefit seen with the omicron BA1-2 variant which is dominating in many regions. There are no clinical data on combination treatment, and currently the GDG advises against combining antivirals in the absence of supporting evidence.
Updates to prior recommendations
The conditional (weak) recommendation for remdesivir in patients with non-severe illness at highest risk of hospitalisation replaces a previous conditional recommendation against treatment with remdesivir in all patients with covid-19 regardless of disease severity. The recommendation for patients with severe or critical illness is being updated using new evidence.
• 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), in combination with corticosteroids; a strong recommendation for baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids; and a conditional recommendation for casirivimab-imdevimab, for those with seronegative status, (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant).
• Recommended for patients with non-severe covid-19—conditional recommendations for those at highest risk of hospitalisation for molnupiravir; sotrovimab; and for casirivimab-imdevimab (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant).
• 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; and a conditional recommendation against ruxolitinib and tofacitinib.
• Not recommended, regardless of covid-19 disease severity—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 new recommendations on two drugs 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 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, with a summary version here in