Therapeutics and COVID-19: living guideline, 14 July 2022

Therapeutics and COVID-19 LIVING GUIDELINE 14 JULY 2022 {mf~~\ World Health ~•t! Organization guideline © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). 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Otherwise, this interim guidance document will expire 2 years after the date of publication. Sections 1. Summary of the guideline .................................................................................................................................................................................................... 5 2. Abbreviations .......................................................................................................................................................................................................................... 7 3. Introduction ............................................................................................................................................................................................................................ 8 4. What triggered this update and what is coming next? .................................................................................................................................................. 9 5. Understanding and applying the WHO severity definitions ......................................................................................................................................10 6. Recommendations for therapeutics .................................................................................................................................................................................11 6.1 Overview of drugs, recommendations and key issues to consider when applying them .........................................................................11 6.2 Fluvoxamine (published 14 July 2022) .................................................................................................................................................................13 6.2.1 Mechanism of action ...................................................................................................................................................................................19 6.3 Colchicine (published 14 July 2022) .....................................................................................................................................................................20 6.3.1 Mechanism of action ...................................................................................................................................................................................23 6.4 Nirmatrelvir-ritonavir (published 22 April 2022) ...............................................................................................................................................23 6.4.1. Mechanism of action ..................................................................................................................................................................................35 6.5 Remdesivir (published 22 April 2022) ..................................................................................................................................................................36 6.5.1 Mechanism of action ...................................................................................................................................................................................43 6.6 Molnupiravir (published 3 March 2022) ..............................................................................................................................................................43 6.6.1 Mechanism of action ...................................................................................................................................................................................49 6.7 Janus kinase inhibitors (published 14 January 2022) .......................................................................................................................................50 6.7.1 Mechanism of action ...................................................................................................................................................................................61 6.8 Sotrovimab (published 14 January 2022) ............................................................................................................................................................62 6.8.1 Mechanism of action ...................................................................................................................................................................................68 6.9 Convalescent plasma (published 7 December 2021) ........................................................................................................................................68 6.9.1 Mechanism of action ...................................................................................................................................................................................75 6.10 Casirivimab-imdevimab (neutralizing monoclonal antibodies) (published 24 September 2021) ........................................................76 6.10.1 Mechanism of action .................................................................................................................................................................................86 6.11 Interleukin-6 receptor blockers (published 6 July 2021) ...............................................................................................................................87 6.11.1 Mechanism of action .................................................................................................................................................................................93 6.12 Ivermectin (published 31 March 2021) .............................................................................................................................................................94 6.12.1 Mechanism of action .................................................................................................................................................................................99 6.13 Hydroxychloroquine (published 17 December 2020) ....................................................................................................................................99 6.14 Lopinavir-ritonavir (published 17 December 2020) .................................................................................................................................... 104 6.15 Systemic corticosteroids (published 2 September 2020) ........................................................................................................................... 108 7. Methods: how this guideline was created ................................................................................................................................................................... 118 8. How to access and use this guideline ........................................................................................................................................................................... 122 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 3 of 142 9. Uncertainties, emerging evidence and future research ............................................................................................................................................ 125 10. Authorship, contributions, acknowledgements ....................................................................................................................................................... 128 References ............................................................................................................................................................................................................................... 133 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 4 of 142 1. Summary of the 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 randomized controlled trials (RCTs) recently completed and underway. This update adds new recommendations on fluvoxamine and colchicine in patients with non-severe COVID-19; the former was informed by a systematic review of three RCTs with 2196 patients, and the latter by 13 RCTs with 18 172 patients. New recommendations: The Guideline Development Group (GDG) recommends not to use fluvoxamine in patients with non-severe illness, except in the context of a clinical trial. A strong recommendation was made against administering colchicine in patients with non-severe illness. No recommendation was made in patients with severe or critical illness as there are limited or no data on either drug for this population. Several treatment alternatives are now available for patients with non-severe COVID-19 at highest risk of hospitalization. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis (LNMA) have been used (see Section 7 for Methods) to inform 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), co-administered medications, duration of treatment, and time from onset of symptoms to starting treatment in the trials. 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. When recommending against the use of fluvoxamine for patients with non-severe illness except in the context of a clinical trial, the GDG recognized the lack of a clear mechanism of action supporting its efficacy, and low to moderate certainty evidence suggesting little or no effect on hospitalization, mechanical ventilation, and mortality. The panel also noted the absence of reliable data on related serious adverse events, known significant pharmacological interactions, and the large proportion of drug discontinuations in included studies. The panel did not anticipate important variability in patient values and preferences regarding using fluvoxamine, and therefore recommended not to use the drug except in the context of a clinical trial. When recommending against the use of colchicine for patients with non-severe illness, the GDG underscored the evidence showing little or no effect on hospitalization, mechanical ventilation, and mortality (moderate certainty). The GDG also discussed the known risks of drug interactions, and colchicine's narrow therapeutic window, particularly in patients with or at risk of hepatic and renal failure. Colchicine toxicity can be severe, and sometimes fatal. Prior recommendations: Recommended for patients with severe or critical COVID-19: • a strong recommendation for systemic corticosteroids; • a strong recommendation for interleukin-6 (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; • a conditional recommendation for casirivimab-imdevimab for patients with seronegative status, where rapid viral genotyping is available and confirms infection with a susceptible SARS-CoV-2 variant. Recommended for patients with non-severe COVID-19 at highest risk of hospitalization: • a strong recommendation for nirmatrelvir-ritonavir; • a conditional recommendation for molnupiravir; • a conditional recommendation for sotrovimab; • a conditional recommendation for casirivimab-imdevimab, where rapid viral genotyping is available and confirms infection with a susceptible SARS-CoV-2 variant; • a conditional recommendation for remdesivir. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 5 of 142 Not recommended for patients with non-severe COVID-19: • a conditional recommendation against systemic corticosteroids; • a strong recommendation against convalescent plasma. Not recommended for patients with non-severe COVID-19 at low risk of hospitalization: • a conditional recommendation against nirmatrelvir-ritonavir. Not recommended for patients with severe and critical COVID-19: • a recommendation against convalescent plasma, except in the context of a clinical trial; • 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; • 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 fluvoxamine and colchicine for patients with non-severe COVID-19. The GDG typically evaluates a drug 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. It is supported by LNMAs (1)(2)(3). Updates and access: This is the eleventh version (tenth update) of the living guideline. It replaces earlier versions (2 September 2020, 20 November 2020, 17 December 2020, 31 March 2021, 6 July 2021, 24 September 2021, 7 December 2021, 14 January 2022, 3 March 2022 and 22 April 2022). The current guideline and its earlier versions are available through the WHO website (4), the BMJ (5), and MAGICapp (online and also as PDF outputs for readers with limited internet access). The living guideline is written, disseminated, and updated in an online platform (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 updated within the guideline. This living WHO guideline for COVID-19 treatments is related to the larger, more comprehensive guideline for COVID-19 clinical management (6). Guidelines for the use of drugs to prevent (rather than treat) COVID-19 are published separately on the WHO website (7) and by the BMJ (8), supported by a LNMA (9). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 6 of 142 2. Abbreviations ALT alanine aminotransferase ARDS acute respiratory distress syndrome CAP community-acquired pneumonia CI confidence interval COVID-19 coronavirus disease 2019 DOI declaration of interests eGFR estimated glomerular filtration rate FDA United States Food and Drug Administration GDG Guideline Development Group GI gastrointestinal GRADE Grading of Recommendations Assessment, Development and Evaluation GRC guideline review committee IL-6 interleukin-6 IMV invasive mechanical ventilation JAK Janus kinase LNMA living network meta-analysis LMIC low- and middle-income countries MAGIC Magic Evidence Ecosystem Foundation MD mean difference OIS optimal information size OR odds ratio PICO population, intervention, comparator, outcome PMA prospective meta-analysis RCT randomized controlled trial RR relative risk/risk ratio SAE serious adverse event SSRI selective serotonin reuptake inhibitor TACO transfusion-associated circulatory overload TRALI transfusion-related acute lung injury WHO World Health Organization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 7 of 142 3. Introduction Info Box As of May 2022, there have been over 524 million confirmed cases of COVID-19 (10). The pandemic has thus far claimed approximately 6.2 million lives (10). Vaccination is having a substantial impact on hospitalizations and death in a number of high- income countries, but limitations in global access to vaccines mean that many populations remain vulnerable (10)(11). Even in vaccinated individuals, uncertainties remain about the duration of protection and effectiveness of current vaccines – and the efficacy of existing treatments for COVID-19 – against emerging SARS-CoV-2 variants. Taken together, there remains a need for more effective treatments for COVID-19. The COVID-19 pandemic – and the explosion of both research and misinformation – has highlighted the need for trustworthy, accessible, and regularly updated living guidance to place emerging findings into context and provide clear recommendations for clinical practice (12). This living guideline responds to emerging evidence from RCTs on existing and new drug treatments for COVID-19. More than 5000 trials investigating interventions for COVID-19 have been registered and are ongoing or completed (see Section 9 for emerging evidence and linked appendix) (13). Among these are large national and international platform trials (such as ACCT, RECOVERY, WHO SOLIDARITY, REMAP-CAP, and ACTIV), which recruit large numbers of patients in many countries, with a pragmatic and adaptive design (14)(15)(16)(17). An overview of ongoing trials is available from the Infectious Diseases Data Observatory, through their living systematic review of COVID-19 clinical trial registrations (13) and the WHO website. Several LNMAs associated with this guideline incorporate emerging trial data and allow for analysis of comparative effectiveness of multiple COVID-19 treatments. To inform the living guidance, we also use additional relevant evidence on safety, prognosis, and patient values and preferences related to COVID-19 treatments. A recently updated living systematic review of 232 risk prediction models in hospitalized patients with COVID-19 identified two promising risk prediction tools that could inform recommendations in this eleventh version of the guideline; these include the Jehi diagnostic model and the 4C mortality model (see Section 6.1 for more details) (18). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 8 of 142 4. What triggered this update and what is coming next? This eleventh version of the WHO living guideline addresses the use of fluvoxamine and colchicine in non-severe COVID-19. It follows the availability of three and seven RCTs, respectively, which were incorporated in an update to the LNMA on drug treatments for COVID-19 (1) . Fig. 1 shows other therapeutics in progress for this WHO living guideline, also communicated through the WHO portal (4). Each dot represents a week of time. In deciding which therapeutics to cover, the WHO considers multiple factors, including the extent of available evidence to inform recommendations, and makes a judgment on whether and when additional evidence might be anticipated. The WHO has a standing Steering Committee (see Section 10) to evaluate possibilities for new drug recommendations and updates to existing drug recommendations. Fig. 1. COVID-19 therapeutics under assessment Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 9 of 142 5. Understanding and applying the WHO severity definitions Info Box This guideline applies to all patients with COVID-19. Recommendations may differ based on the severity of COVID-19, according to WHO severity definitions (see below) (6). These definitions avoid reliance on access to health care to define patient subgroups. WHO definitions of disease severity for COVID-19 • Critical COVID-19 – Defined by the criteria for acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation (invasive or non-invasive) or vasopressor therapy. • Severe COVID-19 – Defined by any of: ◦ oxygen saturation < 90% on room air; ◦ signs of pneumonia; ◦ signs of severe respiratory distress (in adults, accessory muscle use, inability to complete full sentences, respiratory rate > 30 breaths per minute; and, in children, very severe chest wall in-drawing, grunting, central cyanosis, or presence of any other general danger signs including inability to breastfeed or drink, lethargy, convulsions or reduced level of consciousness). • Non-severe COVID-19 – Defined as the absence of any criteria for severe or critical COVID-19. Caution: The GDG noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary, and should be interpreted cautiously when defining disease severity. For example, clinicians must use their judgment to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient with chronic lung disease. Similarly, clinicians may interpret a saturation of 90–94% on room air as abnormal in the patient with normal lungs, and as an early sign of severe disease in patients with a downward clinical trajectory. Generally, in cases wherethere is doubt, the GDG suggested erring on the side of considering disease as severe. The infographic illustrates these three disease severity groups and key characteristics to apply in practice. Infographic co-produced by the BMJ and MAGIC; designer Will Stahl-Timmins (see BMJ Rapid Recommendations). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 10 of 142 6. Recommendations for therapeutics Considerations for decision-making 6.1 Overview of drugs, recommendations and key issues to consider when applying them Info Box The infographic summarizes WHO recommendations, mapped against the WHO severity criteria. When applying the recommendations, clinicians should also consider the following key issues: How to choose between therapeutics Several treatment alternatives are available for patients with non-severe COVID-19, and for those with severe or critical COVID-19. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir and the monoclonal antibodies), co-administered medication, duration of treatment, and time from onset of symptoms to starting treatment in the trials. Some can be used in combination (i.e. as for severe or critical COVID-19) while others are to be used as alternatives. Recommended combinations of treatments are based on direct comparisons from trials demonstrating additional benefit, such as adding baricitinib or interleukin-6 receptor blockers to systemic corticosteroids in patients with severe or critical COVID-19. In the absence of direct comparisons of the various therapeutics in trials, indirect comparisons from the LNMA have been used (see Section 7 - Methods) to inform use of one drug over another with a related mechanism of action. To display the benefits and harms for the alternative therapeutics we provide an interactive decision support tool that can also be used in shared decision-making. Efficacy may vary in the function of specific SARS-CoV-2 variants. For example, previously recommended antibodies may be less effective for the Omicron BA.1/BA.2 variant. How to identify patients with non-severe COVID-19 at highest risk of hospitalization. Several recommendations for drugs are only for those at highest risk for hospitalization because the benefit would be trivial (in absolute terms) if everyone with non-severe COVID-19 were to receive treatment; instead, some treatments should be reserved for those at highest risk of hospitalization and given early in the disease course. The panel identified a risk beyond 10% of being hospitalized for COVID-19 to represent a threshold at which most patients with non-severe illness would want to be treated (see Section 7). Reliably identifying those at highest risk is challenging because of the changing global context with evolution of the virus and patterns of vaccination, thus raising importance of validation of models to local context. A living systematic review of 232 risk prediction models for COVID-19 identified two promising risk prediction tools (18) before Omicron circulation. These tools concur that typical characteristics of people at highest risk include those with older age, immunosuppression and/or chronic diseases, with lack of vaccination as an additional risk factor to consider. Updated Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 11 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 12 of 142 6.2 Fluvoxamine (published 14 July 2022) For patients with non-severe COVID-19 Practical Info The GDG made a recommendation against using fluvoxamine for treatment of patients with COVID-19 outside the setting of a clinical trial and therefore practical considerations are less relevant for this drug. Evidence To Decision Only in research settings We recommend not to use fluvoxamine, except in the context of a clinical trial (recommended only in research settings). • Several therapeutic options are recommended for patients with non-severe COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. • For choosing between the therapeutic options, see Section 6.1 and the decision support tool, which displays benefits and harms of the options. New In patients with non-severe COVID-19, fluvoxamine probably has little or no effect on mortality and may have little or no effect on mechanical ventilation and hospitalization, with no data reported for time to symptom resolution and adverse Benefits and harms Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 13 of 142 Justification When moving from evidence to the recommendation not to use fluvoxamine in patients with non-severe COVID-19 except in the context of a clinical trial, the GDG emphasized the lack of a clear mechanism of action and the low certainty evidence suggesting little to no effect on hospitalization and mechanical ventilation, moderate certainty evidence of little or no effect on mortality, as well as the absence of reliable data on serious adverse effects attributable to the drug known for significant pharmacological interactions. The panel noted that in the largest trial more patients discontinued the investigational product in the fluvoxamine group than in the placebo group. Noting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did not anticipate important variability in patient values and preferences. The panel also did not believe that other considerations, such as resource considerations, accessibility, feasibility, and equity (see summary of these factors under Evidence to Decision) impacted this specific recommendation. Applicability Special populations: None of the included studies enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did not see a reason to assume that children with COVID-19 would respond any differently to treatment with fluvoxamine. effects leading to drug discontinuation. The GDG concluded that the balance between benefits and potential harms does not favour treatment. The planned subgroup analyses for fluvoxamine versus standard care for age and time of symptom onset did not support any differences in relative effects, whereas disease severity could not be performed since trials only enrolled patients with non-severe COVID-19. The evidence summary was informed by 3 trials with 2225 participants included in the LNMA. The largest trial (n=1480) exclusively enrolled patients in Brazil (19). Certainty of evidence was rated as: moderate for mortality (due to serious indirectness), and low for mechanical ventilation (due to serious indirectness, imprecision, and some concerns regarding risk of bias) and hospitalization (due to serious imprecision and risk of bias). Acknowledging that its evaluation of the certainty of the evidence may differ from other published meta-analyses (20), panel members pointed out that early stopping due to apparent benefit may have biased the results of the largest trial. They argued that, although the stopping rules were pre-specified, the decision was based on the effect estimate on a composite outcome of questionable importance, meanwhile the number of important events was lower. The panel also raised concerns regarding the uncertain applicability of this trial conducted in a single country. Certainty of the Evidence Given the agreed upon values and preferences statement (see Section 7), the GDG inferred that almost all well-informed patients would choose not to receive fluvoxamine therapy for COVID-19 based on the available evidence. The GDG did not believe that other considerations, such as feasibility, acceptability, equity and cost, would impact this specific recommendation. Specifically, the GDG did not consider the potential role of fluvoxamine as an antidepressant for this guideline of medications for COVID-19. Values and preferences The panel acknowledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which could limit their availability in resource-constrained areas. However, although fluvoxamine is relatively inexpensive, compared with other drugs used for COVID-19, and widely available, including in low-income settings, the evidence does not justify the use of fluvoxamine for non-severe COVID-19 anywhere. Although the cost of fluvoxamine may be low, the GDG panel raised concerns regarding the risk of diverting attention and resources away from interventions that are more likely to provide a benefit. To avoid the risk of writing recommendations that would risk perpetuating and legitimizing unequal access to more effective drugs, the panel believed that it would be preferable to emphasize the need for more equitable access to effective therapeutic options. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 14 of 142 Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: No fluvoxamine Summary The LNMA for fluvoxamine was informed by three RCTs which enrolled 2225 patients with non-severe illness in outpatient settings. All three RCTs were registered, and two were published in a peer-reviewed journal. All three studies were conducted in outpatients. None of the included studies enrolled children. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of fluvoxamine compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Based on data from the TOGETHER trial (19), no credible subgroup effects were observed on the primary outcome by age (children vs adults vs older adults) and time from symptom onset (0–3 days vs 4–7 days). Planned subgroup analyses for disease severity, age and chronic conditions (absolute effects), serological status and vaccination status were precluded by lack of available data. Outcome Timeframe Study results and measurements Comparator No fluvoxamine Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.68 (CI 95% 0.33 — 1.32) Based on data from 1649 participants in 2 studies. (Randomized controlled) 4 per 1000 Difference: 3 per 1000 1 fewer per 1000 ( CI 95% 3 fewer — 1 more ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation Odds ratio 0.73 (CI 95% 0.38 — 1.4) Based on data from 1649 participants in 2 studies. (Randomized controlled) 18 per 1000 Difference: 13 per 1000 5 fewer per 1000 ( CI 95% 11 fewer — 7 more ) Low Due to serious indirectness and imprecision 2 There may be little or no difference in mechanical ventilation Hospital admission High risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 35 per 1000 Difference: 25 per 1000 10 fewer per 1000 ( CI 95% 23 fewer — 8 more ) Low Due to very serious imprecision 3 Fluvoxamine may reduce hospitalization Hospital admission Higher risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 60 per 1000 Difference: 43 per 1000 17 fewer per 1000 ( CI 95% 39 fewer Low Due to very serious imprecision 4 Fluvoxamine may reduce hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 15 of 142 — 13 more ) Outcome Timeframe Study results and measurements Comparator No fluvoxamine Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: serious. 3. Imprecision: very serious. The credible interval includes both important harm and important benefit.. 4. Imprecision: very serious. The credible interval includes both important harm and important benefit. 5. Imprecision: very serious. The credible interval includes both important harm and important benefit. Hospital admission Highest risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 100 per 1000 Difference: 72 per 1000 28 fewer per 1000 ( CI 95% 64 fewer — 20 more ) Low Due to very serious imprecision 5 Fluvoxamine may reduce hospitalization Adverse effects leading to drug discontinuation No data The effect of fluvoxamine is unknown Time to symptom resolution No data The effect of fluvoxamine is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 0 per 1000 Difference: 3 per 1000 3 more per 1000 ( CI 95% 1 more — 5 more ) Very low Due to serious indirectness, imprecision, and serious risk of bias 1 The impact on mortality is very uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 16 of 142 Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. The EPIC-HR study was stopped early for benefit. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: serious. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study (EPIC-HR) was stopped early for benefit. Imprecision: serious. Mechanical ventilation No data 2 The effect on mechanical ventilation is unknown Hospital admission Odds ratio 4.54 (CI 95% 1.32 — 12.78) (Randomized controlled) 5 per 1000 Difference: 22 per 1000 17 more per 1000 ( CI 95% 2 more — 55 more ) Low Due to serious imprecision and risk of bias 3 Nirmatrelvir-ritonavir may reduce hospitalization more than fluvoxamine Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 5.74 (CI 95% 0.95 — 56.11) (Randomized controlled) 0.4 per 1000 2 per 1000 Low Due to serious indirectness and There may be little or no difference in mortality Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 17 of 142 imprecision 1 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: very serious. 3. Imprecision: very serious. The credible interval includes both important harm and important benefit. Difference: 1.6 more per 1000 ( CI 95% 0.02 fewer — 21.56 more ) Mechanical ventilation Odds ratio 1.77 (CI 95% 0.19 — 10.6) (Randomized controlled) 8 per 1000 Difference: 14 per 1000 6 more per 1000 ( CI 95% 6 fewer — 71 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect on mechanical ventilation is uncertain Hospital admission Odds ratio 1.31 (CI 95% 0.52 — 2.98) (Randomized controlled) 19 per 1000 Difference: 25 per 1000 6 more per 1000 ( CI 95% 9 fewer — 36 more ) Low Due to very serious imprecision 3 There may be little or no difference in hospital admission Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Remdesivir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 18 of 142 6.2.1 Mechanism of action Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) approved as an antidepressant. The antidepressant effects of fluvoxamine are related to inhibition of the serotonin transporter in the brain, which serves to increase the concentrations of serotonin in the synaptic cleft. In COVID-19, several putative anti-inflammatory or antiviral mechanisms of action have been proposed (21)(22). First, anti-inflammatory properties have been postulated as a result of serotonin transporter inhibition in Outcome Timeframe Study results and measurements Comparator Remdesivir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: very serious. 3. Imprecision: very serious. Mortality Odds ratio 0.87 (CI 95% 0.27 — 2.85) (Randomized controlled) 3 per 1000 Difference: 3 per 1000 0 fewer per 1000 ( CI 95% 2 fewer — 6 more ) Low Due to serious indirectness and serious imprecision 1 There may be little or no difference in mortality Mechanical ventilation Odds ratio 1.63 (CI 95% 0.19 — 11.23) (Randomized controlled) 8 per 1000 Difference: 13 per 1000 5 more per 1000 ( CI 95% 6 fewer — 75 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect on mechanical ventilation is uncertain Hospital admission Odds ratio 2.76 (CI 95% 0.62 — 12.07) (Randomized controlled) 9 per 1000 Difference: 24 per 1000 15 more per 1000 ( CI 95% 3 fewer — 90 more ) Low Due to very serious imprecision 3 Remdesivir may reduce hospitalization more than fluvoxamine Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 19 of 142 platelets and/or lungs, but this is based upon indirect evidence from non-COVID-19 disease models. Secondly, host-directed antiviral properties have been proposed via agonism of the sigma-1 receptor, for which some evidence exists from other viruses for an involvement in RNA replication, but there are currently no published preclinical studies that directly demonstrate or refute a mechanism in COVID-19. Therefore, plausibility requires interpretation of indirect evidence for anti-inflammatory or antiviral mechanisms, which are currently unproven preclinically and not directly related to the mechanism and site of action in depression. 6.3 Colchicine (published 14 July 2022) For patients with non-severe COVID-19 Practical Info The GDG made a strong recommendation against using colchicine for treatment of patients with non-severe COVID-19 and therefore practical considerations are less relevant. Evidence To Decision Strong recommendation against We recommend against treatment with colchicine (strong recommendation against). • Several therapeutic options are recommended for patients with non-severe COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. • For choosing between the therapeutic options, see Section 6.1 and the decision support tool, which displays benefits and harms of the options. New In patients with non-severe COVID-19, colchicine probably has little or no impact on mortality and mechanical ventilation, may have little or no impact on hospitalizations, and may increase the likelihood of adverse effects leading to drug discontinuation. The panel discussed the risk of drug interactions and colchicine's narrow therapeutic window, particularly in patients with or at risk of hepatic and renal failure. Colchicine toxicity can be severe, and sometimes fatal. The planned subgroup analyses for colchicine versus standard care did not show different relative effects for disease severity, and age (children, adults, older) with no data reported from illness onset. Benefits and harms The evidence summary on colchicine was informed by a systematic review including 13 trials with 18 172 participants. The evidence was most abundant for mortality with incomplete reporting for other outcomes (e.g. five trials with 598 participants for adverse effects). A single trial of 4488 participants (23), which contributed almost all of the evidence on hospitalizations, was stopped prematurely. Certainty of evidence was rated as: moderate for mortality and mechanical ventilation (rated down for indirectness); low for admission to hospital (rated down for imprecision and risk of bias); and low for adverse effects leading to drug discontinuation (rated down for imprecision and risk of bias). Certainty of the Evidence Given the agreed upon values and preferences statement (see Section 7), the GDG inferred that almost all well-informed patients would choose not to receive colchicine based on available evidence regarding relative benefits and harms. The GDG did not believe that other considerations, such as feasibility, acceptability, equity, and cost, impacted this specific recommendation. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 20 of 142 Justification When moving from evidence to the strong recommendation against the use of colchicine for patients with non-severe COVID-19, the GDG emphasized the moderate certainty evidence of no effect on mortality and mechanical ventilation, and the low certainty evidence of no effect on hospitalizations, but possible harm associated with treatment. Specifically, the panel recognized the risks of diarrhoea, cytopenia, and other toxicities, particularly among patients with, or at risk of, renal failure, as potentially important to patients with non-severe COVID-19. Noting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did not anticipate important variability in patient values and preferences. The panel also did not believe that other considerations, such as resource considerations, accessibility, feasibility, and equity (see summary of these factors under Evidence to Decision) impacted this specific recommendation. Applicability Special populations: None of the included studies enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did not see a reason to assume that children with COVID-19 would respond any differently to treatment with colchicine. The panel acknowledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which could limit their availability in resource-constrained areas. However, although colchicine is relatively inexpensive, compared with other drugs used for COVID-19, and widely available, including in low-income settings, the evidence does not justify the use of colchicine for non-severe COVID-19 anywhere. Although the cost of colchicine may be low, the GDG raised concerns regarding the risk of diverting attention and resources away from interventions that are more likely to provide a benefit. To avoid writing recommendations that would risk perpetuating and legitimizing unequal access to more effective drugs, the panel believed that it would be preferable to emphasize the need for more equitable access to effective therapeutic options. Resources and other considerations Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Colchicine Comparator: Standard care Summary The systematic review for colchicine included 13 trials that enrolled 18 172 patients. All but three trials were registered. None of the studies enrolled children. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of colchicine compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Based on data from the COLCORONA trial (23), no credible subgroup effects were observed on the primary outcome by age (children vs adults vs older adults) and disease severity (non-severe vs severe). Planned subgroup analyses for time from symptom onset, age and chronic conditions (absolute effects), serological status and vaccination status were precluded by lack of available data. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Colchicine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.84 (CI 95% 0.5 — 1.17) Based on data from 17 914 participants in 10 studies. (Randomized 4 3 Moderate Due to serious indirectness 1 Colchicine probably has little or no impact on mortality Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 21 of 142 per 1000 per 1000 controlled) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Colchicine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. 2. Indirectness: serious. Imprecision: no serious. Credible interval includes modest benefit. 3. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 4. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 5. Imprecision: very serious. 6. Risk of bias: serious. Imprecision: serious. ( CI 95% 2 fewer — 1 more ) Mechanical ventilation Odds ratio 0.75 (CI 95% 0.37 — 1.26) Based on data from 12 746 participants in 5 studies. (Randomized controlled) 9 per 1000 Difference: 7 per 1000 2 fewer per 1000 ( CI 95% 6 fewer — 2 more ) Moderate Due to serious indirectness 2 Colchicine probably has little or no impact on mechanical ventilation Admission to hospital Risk in trials Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 35 per 1000 Difference: 24 per 1000 11 fewer per 1000 ( CI 95% 25 fewer — 19 more ) Moderate Due to serious imprecision 3 Colchicine probably has little or no impact on hospital admission Admission to hospital Higher risk Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 60 per 1000 Difference: 42 per 1000 18 fewer per 1000 ( CI 95% 43 fewer — 31 more ) Moderate Due to serious imprecision 4 Colchicine probably has little or no impact on hospital admission Admission to hospital Highest risk Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 100 per 1000 Difference: 70 per 1000 30 fewer per 1000 ( CI 95% 71 fewer — 49 more ) Low Due to very serious imprecision 5 Colchicine may have little or no impact on hospital admission Adverse effects leading to drug discontinuation Based on data from 598 participants in 5 studies. (Randomized controlled) 0 per 1000 Difference: 34 per 1000 34 more per 1000 Low Due to serious risk of bias and serious imprecision 6 Colchicine may increase the risk of adverse effects leading to drug discontinuation Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 22 of 142 Difference: 1 fewer per 1000 6.3.1 Mechanism of action Colchicine is an anti-inflammatory drug used to treat gout, recurrent pericarditis, familial Mediterranean fever, and other inflammatory indications. There are several proposed mechanisms of action that are theorized to obviate inflammation- associated pathology seen in COVID-19 (24)(25), which include a reduction in chemotaxis of neutrophils, inhibition of inflammasome signalling, and decreased production of cytokines such as interleukin-1b (IL-1b). There are no published data at the time when the guideline was pubished from animal models of SARS-CoV-2 infection to support or refute pre-clinical efficacy or harm of colchicine in associated disease pathology. The mechanism of action is postulated to be similar to that for the indications for which colchicine is already approved, but plausibility of effect in COVID-19 requires assumptions around similarities between COVID-19 and other diseases to be accepted. There are marked differences between trials in terms of the doses and schedules that have been investigated in COVID-19. Within the studies included in the NMA, doses ranged between 0.5 and 2 mg per day, course durations ranged between 6 and 30 days, some studies used once daily dosing, some used twice daily dosing, and others used three times daily dosing. In addition, some studies used dosing schedules which changed throughout the course, starting with one dose or schedule and then changing to a different dose or schedule after a predetermined interval. The pharmacokinetics of colchicine are dose linear between 0.5 mg and 1.5 mg (26)(27) but the substantive variation between studies included in the NMA precludes a robust interpretation of differences in outcome associated with dose and schedule. 6.4 Nirmatrelvir-ritonavir (published 22 April 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (nirmatrelvir-ritonavir for COVID-19, administration of nirmatrelvir-ritonavir for COVID-19, safety and monitoring for patients receiving nirmatrelvir- ritonavir for COVID-19). Here follows a brief summary of key points: • The recommended dose for nirmatrelvir-ritonavir is 300 mg (two 150 mg tablets) of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days, as per the regimen evaluated in large trials informing the recommendation. • In renal insufficiency (GFR 30–59 mL/min) the dose reduction is 150 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days. Info Box Recommendations concerning nirmatrelvir-ritonavir for patients with non-severe COVID-19 were published on 22 April 2022 as the tenth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of two RCTs, as per the LNMA on drug therapies (1). No changes were made for the nirmatrelvir-ritonavir recommendation in this eleventh version of the guideline. Strong recommendation for We recommend treatment with nirmatrelvir-ritonavir (strong recommendation for). • See Section 6.1 for help to identify patients at highest risk. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and monoclonal antibodies. • The GDG concluded that nirmatrelvir-ritonavir represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • The strong recommendation in favour does not apply to pregnant women, children, or those with possible dangerous drug interactions (many drugs interact with nirmatrelvir-ritonavir, see mechanism of action). • Nirmatrelvir-ritonavir should be administered as soon as possible after onset of symptoms, ideally within 5 days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 23 of 142 • Administration should be as early as possible in the time course of the disease. In the included studies, nirmatrelvir-ritonavir was administered within 5 days of disease onset. • The GDG concluded that nirmatrelvir-ritonavir should not be offered to children, breastfeeding or pregnant women with COVID-19. In any patient being considered for nirmatrelvir-ritonavir use, clinicians need to give serious consideration to drug interactions. The Liverpool COVID-19 drug interaction checker may be useful in this regard (28). Evidence To Decision In highest risk patients in whom an appreciable decrease in hospitalization with nirmatrelvir-ritonavir is likely, the benefits clearly outweigh the harms, thus warranting the strong recommendation in favour of the drug. In patients with non-severe COVID-19, nirmatrelvir-ritonavir likely reduces admission to hospital (moderate certainty evidence). It may have little or no impact on mortality (low certainty evidence). There are no data reported for time to symptom resolution or mechanical ventilation. Treatment does not increase the likelihood of adverse effects leading to drug discontinuation (high certainty evidence), though diarrhoea and dysgeusia (loss of taste) have occurred more frequently with nirmatrelvir-ritonavir as compared with placebo. The GDG acknowledged that there was a paucity of information relating to emergence of resistance and much more data were needed to inform the recommendation. Benefits and harms The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC-HR) with 3100 participants included in the LNMA study (1)(29)(30). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to concerns regarding imprecision and risk of bias); low for mortality (rated down due to serious imprecision and indirectness) and high for adverse effects leading to drug discontinuation. We did not rate the certainty of the evidence for diarrhoea and dysgeusia. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (31). Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a higher risk of hospitalization would choose to use nirmatrelvir-ritonavir. Values and preferences Acceptability and feasibility Nirmatrelvir-ritonavir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that nirmatrelvir-ritonavir be reserved for those at higher risk. Obstacles to access in low- and middle-income countries (LMICs) may prove formidable due to cost and availability. Those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments, in the first 5 days of symptoms, and thus less access to the interventions. Therefore, if patients at higher risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 24 of 142 Justification Moderate certainty evidence of a substantial relative risk reduction in hospitalization, and high certainty evidence of no adverse effects requiring drug discontinuation, motivated the strong recommendation in individuals at higher risk of hospitalization. Such individuals are likely to achieve an important reduction in the absolute risk of hospitalization in comparison with those not receiving nirmatrelvir-ritonavir. Alternative or combination therapy The GDG has previously made a conditional recommendation for molnupiravir (see Section 6.6) in the highest risk non-severe population, and in this guideline update a conditional recommendation for remdesivir (see Section 6.5). Indirect comparisons in higher and highest risk patients found nirmatrelvir-ritonavir may reduce hospitalization when compared with molnupiravir (low certainty); however, found little or no difference when compared with remdesivir (low certainty). Without direct data comparisons and low certainty confidence in indirect comparisons, the GDG chose not to make comparative recommendations between drugs, but rather remark that nirmatrelvir-ritonavir may be superior based on its efficacy compared with standard of care (moderate certainty) and then ultimate choice based on practical issues, such as ease of administration and risk profiles. There is no evidence for combining antiviral therapies; the GDG therefore advised against this. Applicability The applicability of this recommendation to children, breastfeeding and pregnant women is currently uncertain, as the included RCTs enrolled only non-pregnant adults. The GDG concluded that nirmatrelvir-ritonavir should not be offered to children, breastfeeding or pregnant women with COVID-19. Prequalification Unit. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options according Access to SARS-CoV-2 diagnostics: Since this recommendation involves ideally administering treatment with nirmatrelvir- ritonavir within 5 days of symptom onset, increasing access and ensuring appropriate use of diagnostic tests is essential for implementation. Thus, availability and use of appropriate SARS-CoV-2 diagnostic tests is needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of rapid diagnostic tests such as antigen-detection assays can improve early diagnosis in the community and in primary health care settings. Health care systems must, however, gain expertise in choosing and implementing rapid tests, choosing those most applicable to their settings. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: No nirmatrelvir-ritonavir Summary The LNMA for nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which enrolled 3100 patients with non-severe illness in outpatient settings. The two RCTs were registered; and one was published in a peer-reviewed journal (30). None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and were randomized within 5 days of symptom onset, and no patients received therapeutic co-interventions, these subgroup analyses could not be performed. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 25 of 142 Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0.04 (CI 95% 0 — 0.67) Based on data from 3100 participants in 2 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 2 fewer ) Low Due to serious imprecision and indirectness 1 Nirmatrelvir-ritonavir may have a small effect on mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 35 per 1000 Difference: 5 per 1000 30 fewer per 1000 ( CI 95% 33 fewer — 21 fewer ) Moderate Due to concerns with risk of bias and imprecision 2 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Higher risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 60 per 1000 Difference: 9 per 1000 51 fewer per 1000 ( CI 95% 56 fewer — 36 fewer ) Moderate Due to concerns with risk of bias and imprecision 3 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 100 per 1000 Difference: 16 per 1000 84 fewer per 1000 ( CI 95% 93 fewer — 59 fewer ) Moderate Due to concerns with risk of bias and imprecision 4 Nirmatrelvir-ritonavir probably reduces hospitalization Adverse effects leading to drug discontinuation Odds ratio 0.48 (CI 95% 0.29 — 0.8) Based on data from 2246 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 26 of 142 1. Indirectness: serious. Some patients may be at substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 events (all in the placebo group); and only one study. 2. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0 (CI 95% 0 — 0.29) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 19 per 1000 Difference: 6 per 1000 13 fewer per 1000 ( CI 95% 17 fewer — 2 fewer ) Low Due to risk of bias and imprecision 2 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 57 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 3 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 33 per 1000 17 per 1000 Low Due to risk of bias and imprecision 4 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 27 of 142 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. 2. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 1000 ( CI 95% 51 fewer — 6 fewer ) Adverse effects leading to drug discontinuation 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High There is little or no difference in the risk of adverse effects leading to drug discontinuation. Time to symptom resolution No data The effect of nirmatrelvir/ritonavir is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 28 of 142 Difference: 40 fewer per Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 29 of 142 For patients with non-severe COVID-19 at low risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in a summary of practical issues. In any patient being considered for nirmatrelvir-ritonavir use, clinicians need to give serious consideration to drug interactions. The Liverpool COVID-19 drug interaction checker may be useful in this regard (28). Evidence To Decision Justification Most patients who contract COVID-19 are at very low risk of hospitalization (under 1%) and at a vanishingly small risk of mortality. Such patients will experience trivial benefits with use of nirmatrelvir-ritonavir. The panel inferred that most such Conditional recommendation against We suggest not to use treatment with nirmatrelvir-ritonavir (conditional recommendation against). • In the GDG's assessment, only a minority of low-risk patients will choose to consider using nirmatrelvir-ritonavir. • Trials on antivirals included patients with some risk factors for hospital admission, resulting in a baseline risk of 3% that the GDG applied to generate the recommendation. The risk of hospitalization is likely to be lower in the general population. • Clinicians should not consider nirmatrelvir-ritonavir in pregnant women, children, or those with possible dangerous drug interactions (note: many drugs interact with nirmatrelvir-ritonavir). In patients with non-severe COVID-19, nirmatrelvir-ritonavir probably reduces admission to hospital. However, in low risk patients, the absolute benefit is very small and unlikely to be important to most patients. Nirmatrelvir-ritonavir probably has little or no impact on mortality. Highly relevant to patients at low risk of hospitalization, studies have reported no data for time to symptom resolution. EPIC-SR did, however, report a very closely related outcome: time to 4 consecutive days of mild or no symptoms. For this analysis, the median time was 13.0 (95% CI 12 to 15) days for nirmatrelvir-ritonavir, and 13.0 (95% CI 11 to 14) days for placebo (p=0.47). Treatment does not increase the likelihood of adverse effects leading to drug discontinuation, though diarrhoea and dysgeusia have occurred more frequently with nirmatrelvir-ritonavir, as compared with placebo. Benefits and harms The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC HR) with 3100 participants included in the LNMA study (1)(29)(30). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to concerns regarding serious imprecision and risk of bias); low for mortality (rated down due to serious imprecision and indirectness) and high for adverse effects leading to drug discontinuation. We did not rate certainty of evidence for diarrhoea and dysgeusia. Certainty of the Evidence The GDG believes that most low risk patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on outcomes they consider important. This consideration is particularly relevant for shortening of the duration of symptoms, for which we have no direct evidence supporting a positive impact of nirmatrelvir-ritonavir. Values and preferences Nirmatrelvir-ritonavir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that nirmatrelvir-ritonavir be reserved for those at highest risk. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 30 of 142 patients would be uninterested in using the drug for these trivial benefits. Thus, for most patients, sufficient risk - and thus sufficient benefit of nirmatrelvir-ritonavir - to make nirmatrelvir-ritonavir use an attractive option will require presence of at least one if not a combination of risk factors. This is particularly true in low-income settings in which resource constraints and feasibility issues will make nirmatrelvir-ritonavir use less attractive. The GDG, nevertheless, was cognizant that there are likely to be an appreciable number of individuals who place a high value on very small reductions in the risk of hospitalization and who would thus choose use of nirmatrelvir-ritonavir; therefore, a conditional rather than strong recommendation was made. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: No nirmatrelvir-ritonavir Summary The LNMA for nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which enrolled 3100 patients with non-severe illness in outpatient settings. The two RCTs were registered; and one was published in a peer-reviewed journal (30). None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and were randomized within 5 days of symptom onset, and no patients received therapeutic co-interventions, these subgroup analyses could not be performed. Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0.04 (CI 95% 0 — 0.67) Based on data from 3100 participants in 2 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 2 fewer ) Low Due to serious imprecision and indirectness 1 Nirmatrelvir-ritonavir may have a small effect on mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 35 per 1000 Difference: 5 per 1000 30 fewer per 1000 ( CI 95% 33 fewer — 21 fewer ) Moderate Due to concerns with risk of bias and imprecision 2 Nirmatrelvir-ritonavir probably reduces hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 31 of 142 Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 events (all in the placebo group); and only one study. 2. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Admission to hospital Higher risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 60 per 1000 Difference: 9 per 1000 51 fewer per 1000 ( CI 95% 56 fewer — 36 fewer ) Moderate Due to concerns with risk of bias and imprecision 3 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 100 per 1000 Difference: 16 per 1000 84 fewer per 1000 ( CI 95% 93 fewer — 59 fewer ) Moderate Due to concerns with risk of bias and imprecision 4 Nirmatrelvir-ritonavir probably reduces hospitalization Adverse effects leading to drug discontinuation Odds ratio 0.48 (CI 95% 0.29 — 0.8) Based on data from 2246 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: Molnupiravir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 32 of 142 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0 (CI 95% 0 — 0.29) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 19 per 1000 Difference: 6 per 1000 13 fewer per 1000 ( CI 95% 17 fewer — 2 fewer ) Low Due to risk of bias and imprecision 2 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 57 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 3 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 33 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 4 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Adverse effects leading to drug discontinuation 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High There is little or no difference in the risk of adverse effects leading to drug discontinuation. Time to symptom resolution No data The effect of nirmatrelvir/ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 33 of 142 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. 2. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 34 of 142 6.4.1. Mechanism of action Nirmatrelvir inhibits the SARS-CoV-2 protease (3CLpro), thereby preventing cleavage of the viral polyprotein which is needed for viral proteins to become functional (32). Inhibition of the protease renders the virus unable to replicate. Nirmatrelvir is co- administered with ritonavir, a HIV protease inhibitor, used in this context to boost the pharmacokinetics of nirmatrelvir but without exerting any direct antiviral activity itself (33). Therefore, the combination should be considered as antiviral monotherapy. Nirmatrelvir was developed as an orally deliverable analogue of an intravenous prodrug (lufotrelvir; PF-07304814). The drug was originally developed for SARS-CoV, and has been subsequently repurposed for SARS-CoV-2. Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 in differentiated normal human bronchial epithelial cells with an EC50 of 0.06 micromolar and an EC90 of 0.18 micromolar (33). In healthy volunteers, plasma maximum concentrations of nirmatrelvir were 2210 ng/mL with a half-life of 6 hours following a 300/100 mg dose of nimatrelvir-ritonavir, and steady-state pharmacokinetics were achieved on day 2 (34) (an EC90 of 0.18 micromolar equates to approximately 90 ng/mL). High doses (300 mg/kg) of unboosted nimatrelvir was active against murine-adapted SARS-CoV-2 in mice but with maximum concentrations higher than those achieved at 300/100 mg doses in healthy human volunteers (33). High doses (250 mg/kg) of unboosted nimatrelvir also had efficacy in SARS-CoV-2-infected Syrian golden hamsters but no pharmacokinetic data are available in this species (35). Based upon genome sequence of Omicron, there appears to be no molecular basis for a loss of activity. Nimatrelvir retains activity against BA.1 Omicron in vitro (36) but in vivo data are currently unavailable. Much more data are required to ascertain the rate at which resistance will emerge for nirmatrelvir. Single amino acid changes introduced into the protease sequence can reduce activity of nirmatrelvir by between 23.6- and 39-fold (34). Mouse hepatitis virus (used as a betacoronavirus surrogate) acquired several mutations under a selective pressure in vitro, and these reduced nirmatrelvir activity by between 4- and 91-fold (34). Two amino substitutions were described in clinical trials, one of which did not impact nirmatrelvir activity. Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 35 of 142 Through its impact on metabolism and clearance, ritonavir is a perpetrator of many drug-drug interactions that will require careful consideration. Short durations of therapy needed in COVID-19 may make drug interactions easier to manage than they are for HIV, but twice daily administration means that the ritonavir dose is double that used in most modern antiretroviral regimens. The impact of ritonavir on metabolism may also outlast dosing by several days. The Liverpool COVID-19 drug interaction checker may constitute a valuable tool for management of drug interactions with nirmatrelvir-ritonavir (28). 6.5 Remdesivir (published 22 April 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (remdesivir for COVID-19, administration of remdesivir for COVID-19, safety and monitoring in patients receiving remdesivir for COVID-19). Here follows a brief summary of the key points: • The recommended dose for remdesivir is one dose daily for 3 consecutive days as intravenous infusion, as per the regimen evaluated in large trials informing the recommendation. Remdesivir is given as 200 mg intravenously on day 1, followed by 100 mg intravenously on days 2 and 3. • Administration should be as early as possible in the time course of the disease. In the included studies, remdesivir was administered within 7 days of disease onset. • It may be reasonable to monitor patients for a brief period following infusion. Any health care workers administering the infusions should follow recommended infection prevention and control recommendations in the outpatient setting. • One should use caution when administering remdesivir to patients with significant liver or kidney disease. • The GDG noted that trials did not enrol children 12 years of age or less with < 40 kg, and thus its use in these children is not recommended. • Additionally, the trials did not enrol pregnant or breastfeeding women. The decision regarding use of this therapeutic should be made between the pregnant person and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and WHO information sheet). Info Box An initial conditional recommendation was made on 20 November 2020, suggesting not to use remdesivir for patients with COVID-19, regardless of illness severity. This was based on data from four RCTs which were available at the time, with 7333 participants hospitalized for COVID-19. In the tenth iteration of the guideline, a new recommendation was made for the use of remdesivir for patients with non-severe illness, The recommendation for patients with severe or critical COVID-19 is under review to be updated shortly. No changes were made to the remdesivir recommendation in this eleventh version of the guideline. Conditional recommendation for We suggest treatment with remdesivir (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk for hospitalization. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies. • The GDG concluded that nirmatrelvir-ritonavir represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • Remdesivir should be administered as soon as possible after onset of symptoms, ideally within 7 days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 36 of 142 Evidence To Decision In patients with non-severe COVID-19, remdesivir probably reduces admission to hospital and and may have little or no impact on mortality. The effect of remdesivir on mechanical ventilation and time to symptom resolution is very uncertain. Treatment probably does not increase the likelihood of adverse effects leading to drug discontinuation. The balance between benefits and potential harms favours treatment, but only in the highest risk group. This is because absolute benefit of remdesivir on hospital admission depends on a given patient's prognosis. The GDG defined a threshold of a 6% absolute reduction in hospital admission to represent what most patients would value as an important benefit. Remdesivir would exert such a benefit in patients at highest risk of hospitalization (above 10% baseline risk), such as older people, or those with immunodeficiencies and/or chronic diseases, further enhanced by lacking vaccination. The conditional recommendation for the use of remdesivir in those at highest risk (above 10% baseline risk) reflects this threshold: 73 fewer hospitalizations per 1000 patients. The planned subgroup analyses for remdesivir versus standard care including age, time of symptom onset and disease severity could not be performed in the absence of subgroup data reported publicly or provided by investigators. There were eight children (12 years or more of age) enrolled in the PINETREE trial (37); however, none died or were hospitalized. Benefits and harms The evidence summary was informed by 5 trials with 2709 participants included in the LNMA, with one trial informing the outcome of hospital admission (1)(37). Certainty of evidence was rated as: moderate for decreased admission to hospital (due to serious imprecision); low for mortality (due to serious imprecision and indirectness); very low for mechanical ventilation (due to extremely serious imprecision and serious risk of bias); and moderate for adverse effects leading to drug discontinuation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (18)(31). See Section 6.1 for more details. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline remdesivir, and only those at highest risk would choose to receive treatment. Values and preferences Acceptability and feasibility Remdesivir is administered as one intravenous infusion daily over 3 consecutive days, representing a feasibility challenge in outpatients aiming to avoid hospital admission. Furthermore, remdesivir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that remdesivir should be reserved for those at highest risk. Obstacles to access in LMICs due to cost, feasibility and availability are of concern (38). Challenges in shared decision- making and in communicating the harms versus benefits of remdesivir may also be increased in LMICs. For example, those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments in the first 7 days of symptoms, and thus less access to the interventions. Therefore, if patients at highest risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 8th invitation to Manufacturers of Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 37 of 142 Justification When moving from evidence to the conditional recommendation to use remdesivir in patients with non-severe COVID-19, the GDG emphasized the benefits on decreased need for hospitalization, along with little or no serious adverse effects attributable to the drug. Feasibility and complexity of administration were also carefully considered, and led to the recommendation for use only in the highest risk patients. Typical characteristics of people at highest risk include older people, or those with immunodeficiencies and/or chronic diseases with being unvaccinated further contributing to risk. Costs and access were important considerations, and the GDG recognizes that this recommendation could exacerbate health inequities. The GDG did not anticipate important variability in patient values and preferences (see Evidence to Decision). Alternative or combination therapy The GDG has previously made a a conditional recommendation for molnupiravir in the highest risk non-severe population, and in this guideline a strong recommendation for nirmatrelvir-ritonavir (see Section 6.2) and a conditional recommendation against nirmatrelvir-ritonavir in the lower risk non-severe population. Indirect comparisons in higher and highest risk patients found remdesivir may reduce hospitalization when compared with molnupiravir (low certainty); and found little or no difference when compared with nirmaltrelvir-ritonanivir (low certainty). Without direct data and low certainty confidence in indirect comparisons the GDG chose not to make comparative recommendations between drugs, but rather remark that nirmatrelvir-ritonavir may be superior based on its efficacy compared with standard of care and that ultimate choice be based on practical issues such as administration and potential drug-drug interactions. There is no evidence for combining antiviral therapies; the GDG therefore advised against this. Applicability Only one of the included trial included children (12 years of age and older), and the numbers were extremely small; therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of remdesivir to pregnant or lactating women. The decision regarding use of this therapeutic should be made between the pregnant individual and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and Practical info tabs). The GDG also had concerns about whether the drug would retain efficacy against emerging variants of concern such as Omicron BA.1 or BA.2. Surveillance is needed for SARS-CoV-2 strains with reduced susceptibility to remdesivir and further research examining the role of combination therapy in severely immunocompromised patients. Until further data are available, we have no reason to believe that activity against known variants will be diminished. therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Pre- qualification Unit. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer treatment with remdesivir within 7n days of symptom onset, increasing access and ensuring appropriate use of diagnostic tests is essential. Thus, availability and use of reliable and timely SARS-CoV-2 diagnostic tests (including the use of nucleic acid amplification tests (NAAT) and antigen-based rapid detection tests (Ag-RDTs)) are needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier access to clinical care, particularly in the community and in primary health care settings. National programmes should optimize their testing systems to reflect local epidemiology, response objectives, available resources and needs of their populations. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 38 of 142 Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 39 of 142 control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: No remdesivir Summary The LNMA for remdesivir was informed by five RCTs which enrolled 2731 patients with non-severe illness in outpatient settings; data was available for 2710 patients. All RCTs were registered; and four were published in peer-reviewed journals (15)(37)(39)(40). One of the included studies enrolled children 12 years of age and over; none included pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of remdesivir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The PINETREE trial was the only study to report subgroups within the non-severe subgroup (37). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age. As all patients were unvaccinated, randomized within 7 days of symptom onset, and did not receive therapeutic co- interventions; these subgroup analyses could not be performed. Of note, for age, 1.4% (n=8) were between 12 and 18 years old in the PINETREE trial, and none died or were hospitalized; no subgroup effect was noted for > 60 vs ≤ 60 years old patients (p=0.78). Outcome Timeframe Study results and measurements Comparator No remdesivir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.68 (CI 95% 0.39 — 1.21) Based on data from 2709 participants in 5 studies. (Randomized controlled) 6 per 1000 Difference: 4 per 1000 2 fewer per 1000 4 fewer — 1 more Low Due to serious indirectness and imprecision 1 Remdesivir may have little or no impact on mortality Mechanical ventilation Odds ratio 0.42 (CI 95% 0.08 — 1.96) Based on data from 261 participants in 2 studies. (Randomized controlled) 8 per 1000 Difference: 3 per 1000 5 fewer per 1000 ( CI 95% 7 fewer — 8 more ) Very low Due to very serious imprecision and serious indirectness 2 The impact of remdesivir on mechanical ventilation is uncertain Admission to hospital Risk in trials 35 per 1000 9 per 1000 Moderate Due to serious imprecision 3 Remdesivir probably reduces hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 40 of 142 Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. Outcome Timeframe Study results and measurements Comparator No remdesivir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Does not meet optimal information size; few events (50 total events). 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. There may be an important difference in mechanical ventilation in these patients. Imprecision: very serious. Credible interval includes important benefit and important harm. Does not meet optimal information size; few events (11 total). 3. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 4. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 5. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 6. Imprecision: serious. 7. Imprecision: extremely serious. (Randomized controlled) Difference: 26 fewer per 1000 ( CI 95% 33 fewer — 4 fewer ) Admission to hospital Higher risk Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. (Randomized controlled) 60 per 1000 Difference: 16 per 1000 44 fewer per 1000 ( CI 95% 56 fewer — 7 fewer ) Moderate Due to serious imprecision 4 Remdesivir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. (Randomized controlled) 100 per 1000 Difference: 27 per 1000 73 fewer per 1000 ( CI 95% 93 fewer — 11 fewer ) Moderate Due to serious imprecision 5 Remdesivir probably reduces hospitalization Adverse effects leading to drug discontinuation Based on data from 1379 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 9 per 1000 9 more per 1000 ( CI 95% 0 more — 21 more ) Moderate Due to serious imprecision 6 There is probably little or no difference in adverse effects leading to drug discontinuation Time to symptom resolution Lower better Based on data from 138 participants in 1 study. (Randomized controlled) 9 days (Median) Difference: 7.2 days (Mean) MD 1.8 fewer ( CI 95% 5.7 fewer — 3.5 more ) Very low Due to extremely serious imprecision 7 The impact of remdesivir on time to symptom resolution is uncertain Clinical Question/ PICO Population: Patients with non-severe COVID-19 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 41 of 142 Intervention: Remdesivir Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 6.55 (CI 95% 1.3 — 53.23) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 0 fewer — 0 fewer Low Due to serious indirectness and imprecision 1 There may be little or no difference in mortality Mechanical ventilation Odds ratio 1.08 (CI 95% 0.12 — 9) (Randomized controlled) 8 per 1000 Difference: 9 per 1000 1 more per 1000 ( CI 95% 13 fewer — 16 more ) Low Due serious risk of bias and indirectness 2 The there may be little or no difference in mechanical ventilation Admission to hospital Risk in trials Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 19 per 1000 Difference: 9 per 1000 10 fewer per 1000 ( CI 95% 17 fewer — 17 more ) Moderate Due to serious imprecision 3 There may be little or no difference in hospital admission Admission to hospital Higher risk Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 33 per 1000 Difference: 16 per 1000 17 fewer per 1000 ( CI 95% 29 fewer — 29 more ) Low Due to very serious imprecision 4 Remdesivir may reduce hospital admission more than molnupiravir Admission to hospital Highest risk Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 57 per 1000 Difference: 28 per 1000 29 fewer per 1000 ( CI 95% 50 fewer — 47 more ) Low Due to very serious imprecision 5 Remdesivir may reduce hospital admission more than molnupiravir Adverse effects leading to drug discontinuation 0 per 1000 Difference: 9 per 1000 9 more per 1000 ( CI 95% 3 fewer — 21 more ) Very low Due to serious risk of bias, imprecision and indirectness 6 The impact on adverse events leading to drug discontinuation is uncertain Time to symptom Lower better (Randomized controlled) 5.6 days (Median) 7.9 days (Mean) Very low Due to extremely serious The impact on time to symptom resolution is very uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 42 of 142 resolution imprecision 7 6.5.1 Mechanism of action Remdesivir was developed for treatment of hepatitis C virus infection, and was also studied in Ebola and Marburg virus infections before being repurposed for SARS-CoV-2. Remdesivir is a nucleoside drug. Its mechanism of action involves chain termination, which is different to lethal mutagenesis: the drug is incorporated preferentially to the endogenous adenosine nucleoside by the SARS-CoV-2 polymerase during replication of the RNA genome. Unlike many other chain-terminating nucleoside drugs used for other viruses, remdesivir elicits delayed chain termination because RNA synthesis is terminated after the addition of three more nucleotides, rather than at the point of remdesivir incorporation (41). Emergence of antiviral resistance: Under a selective pressure in vitro, SAR-CoV-2 resistance to remdesivir emerged and was associated with a mutation (E802D) within the sequence coding for the polymerase (42). The E802D mutation was also reported in a case study describing an immunocompromised patient receiving remdesivir who experienced recrudescence of high-grade viral shedding following a transient virological response to the drug (43). The clinical significance of these observations if remdesivir were widely used in an outpatient setting is unclear. 6.6 Molnupiravir (published 3 March 2022) Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The evidence for molnupiravir was at high risk of bias. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. There may be an important difference in mechanical ventilation in these patients. 3. Imprecision: serious. Credible interval includes important benefit and important harm. 4. Imprecision: very serious. Credible interval includes important benefit and important harm. 5. Imprecision: very serious. Credible interval includes important benefit and important harm. 6. Risk of bias: serious. Indirectness: serious. Imprecision: serious. 7. Imprecision: extremely serious. Difference: MD 2.3 more ( CI 95% 1.9 fewer — 7.8 more ) Info Box Recommendations concerning molnupiravir for patients with non-severe COVID-19 were published on 3 March 2022 as the ninth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of six RCTs, as per the LNMA on drug therapies (1). No changes were made to the molnupiravir recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 43 of 142 For patients with non-severe COVID-19 at highest risk of hospitalization (excluding pregnant and breastfeeding women, and children) Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (molnupiravir for COVID-19, administration of molnupiravir for COVID-19, safety and monitoring for patients receiving molnupiravir for COVID-19). Here follows a brief summary of the key points: • The recommended dose for molnupiravir is 800 mg tablet every 12 hours daily for 5 days, as per the regimen evaluated in large trials informing the recommendation. • Administration should be as early as possible in the time course of the disease. In the included studies, molnupiravir was administered within 5 days of disease onset. Evidence To Decision Conditional recommendation for We suggest treatment with molnupiravir (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk for hospitalization. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies. • The longer-term harms of molnupiravir remain unknown in the absence of clinical evidence, both for individual patients and at the population level. These include genotoxicity, emergence of resistance, and emergence of new variants (see Mechanism of action). • The conditional recommendation reflects the concern for widespread treatment with molnupiravir before more safety data become available. • Use of molnupiravir should be accompanied by mitigation strategies such as avoiding the drug in younger adults, active pharmacovigilance programmes, and monitoring viral polymerase and spike sequences (see Justification). In patients with non-severe COVID-19, molnupiravir probably reduces admission to hospital and time to symptom resolution, and may reduce mortality. The effect of molnupiravir on mechanical ventilation is very uncertain. Treatment does not increase the likelihood of adverse effects leading to drug discontinuation. However, potential long-term harms of molnupiravir remain uncertain and a matter of concern, in the absence of clinical data. Potential harms include emergence of resistance, and the potential harm coming from the risk of molnupiravir-induced mutagenesis. These deliberations (see Justification section) were based on molnupiravir's mechanism of action and available pre-clinical data (see Mechanism of action section). The balance between benefits and potential harms was close, but favoured treatment in the highest risk group, if implemented with other mitigation strategies to avoid harm at individual and population level (see Mitigation strategies section). There is a risk that monotherapy with molnupiravir (as for other antiviral monotherapies) may be associated with emergence of drug resistance, as has been seen with other antivirals (see Mechanism of action section). The absolute benefits of molnupiravir on hospital admission depend on the prognosis. The GDG defined a threshold of a 6% absolute reduction in hospital admission to represent what most patients would value as an important benefit. Molnupiravir would exert such a benefit in patients at highest risk of hospitalization (above 10% baseline risk), such as those that lack COVID-19 vaccination, older people, or those with immunodeficiencies and/or chronic diseases. The conditional recommendation for the use of molnupiravir in those at highest risk reflects this threshold: 60 fewer hospitalizations per 1000 patients, and a greater anticipated absolute survival benefit, although this was not possible to quantify in the absence of data. The planned subgroup analyses could not be performed in the absence of subgroup data reported publicly or provided by investigators. Benefits and harms Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 44 of 142 The evidence summary was informed by six trials with 4796 participants included in the LNMA, including the MOVe-OUT study (44). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to serious imprecision); low for mortality (rated down due to serious imprecision and indirectness); moderate for time to symptom resolution (rated down due to serious risk of bias); very low for mechanical ventilation (rated down due to extremely serious imprecision and serious risk of bias); and high for adverse effects leading to drug discontinuation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (31). In addition, the GDG felt that there was some indirectness because of the possible emergence of variants (including Omicron) for which the effectiveness of currently available monoclonal antibodies may be reduced. The GDG decided against rating certainty down for imprecision for outcomes where low event rates reflected very low baseline risks (e.g. mortality). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline molnupiravir, and only those at highest risk (e.g. unvaccinated, older, or immunosuppressed) would choose to receive treatment. In the absence of research evidence, in a previous survey (see recommendation for casirivimab-imdevimab), the GDG expressed the view that most patients with a risk of hospitalization above 10%, and thus an absolute risk reduction of approximately 6%, would choose to receive treatment, whereas most of those below that risk level would decline treatment. A similar survey was completed by the GDG for this recommendation; the GDG expressed the view that most patients would consider a reduction in the absolute risk of death of 3 per 1000 (increase in survivors from 995 to 998 per 1000 patients) to be important. Values and preferences Acceptability and feasibility Molnupiravir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that molnupiravir should be reserved for those at highest risk. Obstacles to access in LMICs due to cost and availability are of concern (38). Challenges in shared decision-making and in communicating the harms versus benefits of molnupiravir may also be increased in LMICs. For example, those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments, in the first 5 days of symptoms, and thus less access to the interventions. Therefore, if patients at highest risk receive the intervention this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which included molnupiravir. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer treatment with molnupiravir within 5 days of symptom onset; increasing access and ensuring appropriate use of diagnostic tests is essential. Thus, availability and use of reliable and timely COVID-19 diagnostic tests (including the use of NAAT and Ag-RDTs) is needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier access to clinical care, particularly in the Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 45 of 142 Justification A combination of the evidence, safety concerns based on preclinical data, values and preferences, and feasibility contributed to the conditional recommendation for the use of molnupiravir only in patients with non-severe COVID-19 at highest risk of hospitalization. Typical characteristics of people at highest risk include those who are unvaccinated, older people, or those with immunodeficiencies and/or chronic diseases (e.g. diabetes). Only a minority of patients who are at highest risk are likely to achieve sufficient benefit to compensate for the risks, and other limitations and disadvantages of therapy. These include a lack of reliable tools to identify high-risk patients, limited availability of the drug, and the safety concerns summarized below. • The GDG had concerns about the risk of emergent resistance with a new antiviral deployed as monotherapy (see Mechanism of action section). Significant uncertainty exists regarding how quickly resistance will emerge; in the absence of sufficient clinical data, the GDG concluded large uncertainties remain. • Concerning the risk of the drug promoting the emergence of new variants, the GDG noted that there was a low likelihood that the drug would result in a selective pressure for a new variant; large uncertainty remains in the absence of sufficient clinical data. • Molnupiravir is mutagenic in mammalian cells in vitro, but there is no evidence of mutagenicity in animal models or humans. The GDG therefore acknowledged uncertainty regarding longer term genetic toxicity and potential for malignancy associated with molnupiravir. • Given evidence from rat pups of an impact on growth plate thickness, molnupiravir should not be used in children. Similarly, since molnupiravir elicited embryo-fetal lethality and teratogenicity in offspring when given to pregnant animals, it should not be used in pregnant or breastfeeding women. • The GDG acknowledged that spermatogenesis may also be especially prone to the mutagenic effects of molnupiravir, but that there was uncertainty regarding the consequences to children conceived by fathers receiving or having recently received molnupiravir. Applicability The applicability of this recommendation to children, breastfeeding and pregnant women, is currently uncertain, as the included RCTs enrolled only non-pregnant adults. However, the GDG concluded that molnupiravir should not be offered to children, breastfeeding or pregnant women with COVID-19. In addition, men planning to conceive should be oriented on the potential for temporary genotoxic effect on sperm cell production (see Mitigation strategies section). The unknown long-term risk of genotoxicity is likely to be higher in younger patients as compared with older patients, thus its use in younger adults not a high risk should be avoided. The GDG also had concerns about whether the drug would retain efficacy against emerging variants of concern such as Omicron. While there is no molecular basis for a loss of efficacy, the GDG noted that the higher viral loads and associated disease severity may impact the effectiveness of molnupiravir. This represents another area of uncertainty, given currently available data did not include patients with newer variants, including Omicron (see Section 9). community and in primary health care settings. National programs should optimize their testing systems to reflect local epidemiology, response objectives, available resources and needs of their populations. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Molnupiravir Comparator: Standard care Summary Evidence summary The LNMA for molnupiravir was informed by six RCTs which enrolled 4827 patients with non-severe illness in outpatient settings; the LNMA team had access to data for 4796 patients. All RCTs were registered; none were published in peer-reviewed journals. None of the included studies enrolled children or pregnant women. The appendix Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 46 of 142 summarizes study characteristics and risk of bias ratings, effect estimates by outcome and associated forest plots for molnupiravir versus standard care. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of molnupiravir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). Subgroup analysis Five pre-specified subgroup analyses were requested by the GDG: 1. Age: children (≤ 19 years) versus adults (20–60 years) versus older adults (≥ 60 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Time from symptom onset. 4. Serological status (seropositive versus seronegative). 5. Vaccination status (unvaccinated versus vaccinated). Studies did not enrol children, nor patients with severe or critical illness. All studies enrolled unvaccinated individuals with time from symptom onset < 5 days. Data regarding serological status were not reported. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Molnupiravir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.06 (CI 95% 0 — 0.4) Based on data from 4796 participants in 6 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 4 fewer ) Low Due to serious imprecision and indirectness 1 Molnupiravir may have a small effect on mortality Mechanical ventilation Odds ratio 1 (CI 95% 0.02 — 59.74) Based on data from 1220 participants in 1 study. (Randomized controlled) 8 per 1000 Difference: 8 per 1000 0 fewer per 1000 ( CI 95% 8 fewer — 317 more ) Very low Due to serious risk of bias and extremely serious imprecision 2 The effect of molnupiravir on mechanical ventilation is very uncertain Admission to hospital Risk in trials Odds ratio 0.54 (CI 95% 0.3 — 0.89) Based on data from 4688 participants in 5 studies. (Randomized controlled) 35 per 1000 Difference: 19 per 1000 16 fewer per 1000 ( CI 95% 24 fewer — 4 fewer ) Moderate Due to serious imprecision 3 Molnupiravir probably reduces hospital admission Admission to hospital Higher risk Odds ratio 0.54 (CI 95% 0.3 — 0.89) Based on data from 4688 participants in 5 studies. (Randomized controlled) 60 per 1000 Difference: 33 per 1000 27 fewer per 1000 ( CI 95% 41 fewer — 6 fewer ) Moderate Due to serious imprecision 4 Molnupiravir probably reduces hospital admission Admission to Odds ratio 0.54 (CI 95% 0.3 — 0.89) 100 57 Moderate Due to serious Molnupiravir probably reduces hospital Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 47 of 142 per 1000 per 1000 hospital Highest risk imprecision 5 admission Outcome Timeframe Study results and measurements Comparator Standard care Intervention Molnupiravir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, who are not easily identifiable. For these patients, molnupiravir may have an important impact on mortality. Imprecision: serious. There were only 11 events total (10 in the control arms and 1 in the molnupiravir arms). 2. Risk of bias: serious. The single trial reporting mechanical ventilation was not blinded. Imprecision: extremely serious. Very few events, resulted in very large credible intervals that include important and unimportant effects. 3. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 4. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 5. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 6. Risk of bias: serious. All three trials were at high risk of bias for deviations from intended intervention (lack of blinding). One trial was at high risk of bias for possible inadequate randomization concealment. Based on data from 4688 participants in 5 studies. (Randomized controlled) Difference: 43 fewer per 1000 ( CI 95% 68 fewer — 10 fewer ) Adverse effects leading to drug discontinuation Based on data from 4796 participants in 6 studies. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 2 more ) High There is little or no difference in adverse effects leading to drug discontinuation Time to symptom resolution Lower better Based on data from 3078 participants in 3 studies. (Randomized controlled) 9 (Median) Difference: 5.6 (Mean) MD 3.4 fewer ( CI 95% 4.8 fewer — 1.7 fewer ) Moderate Due to serious risk of bias 6 Molnupiravir probably reduces duration of symptoms Malignancy In vitro and animal studies suggest the possibility of carcinogenesis Very low No human data with long-term follow-up The effect of molnupiravir on cancer is uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 48 of 142 Mitigation strategies to address safety concerns 6.6.1 Mechanism of action Molnupiravir an orally available antiviral, which was originally designed as an influenza treatment, although not approved. The drug inhibits replication of SARS-CoV-2 with an in vitro potency broadly, similar to remdesivir, and was re-purposed early in development as an antiviral for SARS-CoV-2 (47)(48). Molnupiravir is an orally available prodrug of ß-D-N4-hydroxycytidine (NHC). It is a nucleoside drug, but the mechanism of action involves lethal mutagensis of the virus. This contrasts with chain-termination seen with other antiviral nucleoside analogues (e.g. remdesivir and those used in HIV or HCV) (49). NHC is incorporated by the SARS-CoV-2 RdRp, instead of either C or U nucleosides, into the genomic or subgenomic RNA during copying of the RNA template genome. The resultant NHC- containing RNAs are then themselves used as a template for production of subsequent RNAs which are predicted to be mutated and therefore not believed to form functional viruses (49)(50). Molnupiravir is given orally twice daily unlike remdesivir, which is given by intravenous infusion once daily. In healthy volunteers, molnupiravir (800mg) achieves maximum plasma concentrations of its active metabolite at 3600 ng/mL (51). This is higher than that of remdesivir (2200 ng/mL) (52). However, the intracellular half-life of molnupiravir active metabolite is shorter in human cell lines (3h) compared with that of remdesivir's active metabolite (35h) (51). High doses of molnupiravir (250 mg/kg twice daily) have been shown to be effective in SARS-CoV-2-infected Syrian golden hamsters; however, the animal plasma pharmacokinetics were not reported to benchmark against those seen in humans (53). Evidence of antiviral activity is also available from a study in SARS-CoV-2-infected ferrets at lower doses (54). When molnupiravir was combined with favipiravir in infected Syrian golden hamsters, the efficacy was greater than when either drug was given alone (55). Molnupiravir retains activity against Alpha and Beta variants in vivo (56), and the Delta and Omicron variants in vitro (57)(58). No data are currently available demonstrating activity against the Delta or Omicron variants in vivo, and while there appears to be no molecular basis for a loss of activity, there is residual uncertainty around whether a higher replication or transmission rate may impact efficacy of the drug. Info Box With the safety concerns related to molnupiravir (see Mechanism of action section), the WHO recognizes the need to mitigate risks, both for individual patients and at the population level. The conditional recommendation takes into account one such strategy: limiting the intervention to patients that are at higher risk of hospitalization or death. Typical characteristics of people at highest risk include those with older age, immunodeficiencies and/or chronic diseases (e.g. diabetes) and lack of COVID-19 vaccination. See WHO recommendations for further information on COVID-19 vaccination Strategic Advisory Group of Experts on Immunization for more details. Other mitigation strategies include: • Decisions around treatment with molnupiravir must be done using a shared decision-making model, ensuring the clinician is well educated on the potential benefits and harms of therapy and able to explain these to the patient in order to make well-informed decisions. See Practical information section. ◦ Molnupiravir should not be given to pregnant or breastfeeding women or to children. In case of doubt about pregnancy, a pregnancy test should be performed prior to treatment initiation. If a woman of child bearing age is considered for treatment, counselling regarding birth control during treatment and for 4 days after the last dose of molnupiravir should be facilitated. ◦ Men planning to conceive should be oriented on the potential for temporary genotoxic effect on sperm cell production, and those who are sexually active with females should be counselled to use birth control during treatment and for at least 3 months after the last dose of molnupiravir (46). ◦ The unknown long-term risk of genotoxicity is likely to be higher in younger patients as compared with older patients; thus use in younger adults who are not at high risk should be limited. • Active sequence monitoring of SARS-CoV-2 detected in clinical respiratory samples (i.e. may include polymerase and spike) should be arranged for patients receiving therapy, including higher risk individuals (immunocompromised). • Pharmacovigilance: use of molnupiravir should be accompanied by a robust, active pharmacovigilance programme. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 49 of 142 Emergence of resistance: The emergence of resistance to drugs used for other viruses is varied; with some resistance emerges readily, and with others emerging more slowly. The barrier to resistance for a given drug with a given virus is generally considered to increase with the number of mutations that are required to emerge. Insufficient data are currently available to ascertain how high the barrier of resistance is with SARS-CoV-2 for molnupiravir. Based on experiences with other nucleoside antiviral drugs (some have a high barrier to resistance and some have a low barrier to resistance), molnupiravir will place a selective pressure for viral resistance mutations within an individual, with the potential to spread at a population level. Non- clinical and/or clinical data are therefore needed, but are not currently available for molnupiravir. Resistance occurs through inherent variability in viral sequences that happen spontaneously as the virus replicates. Chance variations become selected, known as selective pressure, when they confer a survival advantage in the presence of the drug. Sometimes, there is a fitness cost to the virus and secondary mutations can subsequently be selected to restore fitness. The major uncertainty relates to how quickly resistance will emerge rather than whether it will emerge. There may be a higher risk of resistance in immunocompromised patients because of a longer tail of replication in this group. There may also be a higher risk of resistance in patients with poor adherence where the virus is exposed to suboptimal drug concentrations. The rate at which resistance emerges will be slower if drugs are given in combination because more mutations will be required to confer resistance to multiple drugs than will be required for one drug. Of note, animal studies have also demonstrated drug combinations to be more effective. The risk of resistance to individual patients is drug failure due to compromised efficacy. If resistance is transmitted, there is a risk of efficacy failure at a population level and subsequent attempts to combine the drug may be futile because of “functional monotherapy” with the partner agent. The genetic barrier to resistance cannot be estimated without data. Emergence of new variants: It has been proposed that random mutagenesis arising from the molnupiravir mechanism of action might increase diversity in the viral sequences that may result in more rapid emergence of new variants (59). Unlike in the considerations for resistance, there is no conceptual basis for molnupiravir placing a selective pressure on emergence of new variants. Sequence variation is lower given molnupiravir is only incorporated in place of two of the four nucleotide bases in the genome than it would be if incorporated in place of any nucleotide. There is no direct evidence to support or refute the variants hypothesis and as such the risk is currently unquantifiable. The rate of resistance emergence and the risk of additional diversity in the viral genome leading to new variants, were acknowledged to be higher with a higher number of patients receiving the intervention. Non-clinical safety: The GDG reviewed the publically available data on non-clinical safety of molnupiravir from the FDA meeting documents for molnupiravir Emergence Use Authorization (30 November 2021) (60). The following safety concerns were highlighted: • Genetic toxicology data demonstrated that molnupiravir is mutagenic in vitro, but there was no evidence of mutagenicity in animal models. The GDG acknowledged uncertainties in the available data and concluded that based upon the available information molnupiravir may or may not be carcinogenic in humans. • An increase in thickness of growth plate associated with decreased bone formation was observed in rapidly growing rats but not in mice, rats or dogs. The GDG determined that molnupiravir should not therefore be administered to paediatric patients. • Importantly, low concentrations of NHC (0.09% maternal exposures) were detectable in 10-day old rat pups suggesting that NHC is present in breast milk. The GDG determined molnupiravir should not be administered to breastfeeding women. • In developmental and reproductive toxicology assessments, reduced foetal body weights were observed in rats and rabbits, with higher exposures also being associated with embryo-foetal lethality and teratogenicity in rats. Accordingly, molnupiravir should not be administered during pregnancy. • There was an absence of available data relating to spermatogenesis, which may be particularly prone to the effect of a mutagen in adult males. No data are available to quantify the consequences of this for embryo/foetus conceived by fathers who were receiving or had recently received molnupiravir. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 50 of 142 Baricitinib, for patients with severe or critical COVID-19 Practical Info Additional considerations are available in a summary of practical issues. Useful information can also be found in the United States Food and Drug Administration (FDA) fact sheet for health care providers, based on the emergency use authorization (EUA) of baricitinib (61). Here follows a brief summary of key points: Route, dosage and duration: • The recommended dose is 4 mg daily orally in adults with eGFR ≥ 60 mL/min/1.73 m2. • A duration of 14 days of total treatment or until hospital discharge, whichever is first. The optimal duration of treatment is unknown, and the proposed duration reflects what was used in the trials providing evidence on treatment effects of baricitinib. Dose regimen adjustment: • Patients with leukopenia, renal impairment or hepatic impairment (note: these parameters should be monitored during treatment); • Patients taking strong organic anion transporter 3 (OAT3) inhibitors (e.g. probenecid), there are drug interactions which warrant dose reductions. Timing: Baricitinib (like IL-6 receptor blockers) should be initiated at the same time as systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. Evidence To Decision Info Box Recommendations concerning janus kinase (JAK) inhibitors, specifically baricitinib, ruxolitinib and tofacitinib, for patients with severe or critical COVID-19 were published on 14 January 2022 as the eighth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of three RCTs for baricitinib, two RCTs for ruxolitinib, and one RCT for tofacitinib, as per the LNMA on drug therapies (1). No changes were made to the JAK inhibitors recommendations in this eleventh version of the guideline; however, we are aware of recent publication of RECOVERY trial that supports our previous recommendation and are currently reviewing. Strong recommendation for We recommend treatment with baricitinib (strong recommendation for). • Along with baricitinib, corticosteroids should also be administered in patients with severe or critical COVID-19 (see Section 6.15). • IL-6 receptor blockers (tocilizumab or sarilumab) have previously been recommended for the treatment of patients with severe or critical COVID-19 (see Section 6.11). An IL-6 receptor blocker and baricitinib should not be given together, and should be viewed as alternatives. The choice of whether to use baricitinib or an IL-6 receptor blocker depends on availability, as well as clinical and contextual factors (see Justification). Benefits and harms In patients with severe or critical illness, baricitinib probably reduces mortality and duration of mechanical ventilation, and reduces hospital length of stay. It probably results in little or no increase in serious adverse events. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no evidence of a subgroup effect on relative risk in younger (< 70 years) versus older patients; those with critical versus severe Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 51 of 142 6.7 Janus kinase inhibitors (published 14 January 2022) Justification When moving from evidence to the strong recommendation to use baricitinib in patients with severe or critical COVID-19, the GDG emphasized the benefits on survival and decreased length of hospital stay with ease of administration and the likelihood of little or no serious adverse events attributable to the drug. The GDG acknowledged that some serious adverse events, such as fungal infections, may not have been accurately captured during the relatively short follow-up period in the included trials. baseline. Certainty of evidence was rated as: moderate for decreased mortality (rated down from high for a large ongoing trial that may change estimates of effect and indirectness due to the relatively short follow-up period close to 28 days possibly being insufficient to capture all relevant events); high for reduction in hospital length of stay; moderate for reduction in duration of mechanical ventilation and for little or no increase in serious adverse events, both rated down for serious imprecision; and low for need for mechanical ventilation, rated down for very serious imprecision. The GDG noted in particular that the risk of serious infections (bacterial and fungal) may vary considerably in different parts of the world according to the background prevalence of infections (such as tuberculosis). This may not be so important given the short course of baricitinib used for treatment of COVID-19, but evidence is limited given the limited geographic spread of the included trials and short follow-up periods. Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with severe or critical COVID-19 would want to receive baricitinib due to the likely reduction in mortality, and moderate certainty evidence of little or no increase in serious adverse events. The benefit of baricitinib on mortality was deemed of critical importance to patients and the GDG was reassured by the moderate certainty evidence of little or no increase in serious adverse events. The GDG anticipated little variation in values and preferences between patients for this intervention. Values and preferences Resource implications, equity and human rights Compared with some other candidate treatments for COVID-19, baricitinib is expensive. The recommendation does not take account of cost-effectiveness. Access to these drugs is challenging in many parts of the world, and, without concerted effort, is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. On 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which includes baricitinib. At a time of drug shortage, it may be necessary to prioritize use of baricitinib through clinical triage (6) such as prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course, and avoiding baricitinib in those with established multi-organ failure (in whom the benefit is likely to be smaller). Acceptability and feasibility As baricitinib is administered orally once daily, hospitalized patients should find it easy to accept this treatment. In patients who cannot swallow tablets, baricitinib can be crushed, dispersed in water, and given via a nasogastric tube (see Practical info). Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 52 of 142 COVID-19; those receiving and not receiving corticosteroids at baseline; and those receiving and not receiving remdesivir at below). Costs and access were important considerations and the GDG recognizes that this recommendation could exacerbate health inequities. This strong recommendation will provide impetus to address these concerns and maximize access across regions and countries. The GDG did not anticipate important variability in patient values and preferences, and judged that other contextual factors would not alter the recommendation (see Evidence to Decision). Emerging evidence When making the strong recommendation for treatment with baricitinib, The GDG carefully considered the implications of a yet unpublished large trial (RECOVERY) having randomized patients to baricitinib or no baricitinib. Uncertainties regarding this trial included the proportion of patients who also received an IL-6 receptor blocker (see below), and when the information will be available. The GDG considered the benefits of baricitinib, supported by moderate to high certainty evidence, sufficient for an immediate strong recommendation for use of the drug, with readiness to update the living guideline as necessary once RECOVERY trial data are published. The RECOVERY trial is now published (ref) and confirms the beneficial effects of baricitinib in patients with severe and critical COVID-19. The GDG will fully assess the updated evidence for baricitinib once the LNMA has been updated and before the next iteration of the guideline. The role of IL-6 receptor blockers and baricitinib The GDG has previously made a strong recommendation for use of IL-6 receptor blockers (tocilizumab and sarilumab) in patients with severe or critical COVID-19. The GDG carefully considered whether, on the basis of the current evidence, baricitinib should be administered as an alternative to IL-6 receptor blockers or in addition to IL-6 receptor blockers. Combining them may unacceptably increase harms, including secondary bacterial and fungal infections. In the absence of evidence of incremental benefit, the GDG advises that clinicians do not administer the drugs together. The issue then arises regarding the basis for choosing between IL-6 receptor blockers and baricitinib (see Research evidence). The drugs have not undergone direct comparisons, and so the best evidence of their relative effects comes from indirect comparisons generated by the LNMA that informs these guidelines. Baricitinib may reduce mortality relative to IL-6 receptor blockers (low certainty) and may reduce the duration of mechanical ventilation (low certainty). There may be little or no difference in the agents’ impact on mechanical ventilation (low certainty), and there is probably little or no difference in adverse events leading to discontinuation (moderate certainty) (see Summary of Findings table in Research evidence). The GDG felt that the low certainty evidence did not warrant a recommendation favouring the use of baricitinib versus IL-6 receptor blockers on the basis of their impact on patient-important benefits and harms. Therefore, when both agents are available, clinicians should choose between them based on other considerations. These might include experience and comfort using the drugs; local institutional policies; route of administration (baricitinib is oral; IL-6 receptor blockers are intravenous); and cost. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of baricitinib to pregnant or lactating women. The decision regarding use of this therapeutic should be made between the pregnant individual and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and Practical info tabs). Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Baricitinib Comparator: Standard care Summary Evidence summary The LNMA for baricitinib was informed by three RCTs which enrolled 2659 patients across disease severities (62)(63)(64). All RCTs were registered, and two were published in peer-reviewed journals (63)(64); one study was a pre-print (62). All three RCTs enrolled patients in in-patient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 53 of 142 Because of different mechanisms of action, the GDG considered baricitinib separately from other JAK inhibitors (as outlined For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of baricitinib compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Baseline risk estimates For severe and critical illness, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence (see Section 7). Subgroup analysis Four pre-specified subgroup analyses were undertaken for JAK inhibitors as a class rather than for individual drugs: 1. Age: younger adults (< 70 years) versus older adults (≥ 70 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Concomitant use of corticosteroids at baseline. 4. Concomitant use of remdesivir at baseline. No evidence of subgroup effects was identified on the relative risk of critical outcomes across all pre-specified effect modifiers. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.62 (CI 95% 0.44 — 0.85) Based on data from 2659 participants in 3 studies. (Randomized controlled) 130 per 1000 Difference: 85 per 1000 45 fewer per 1000 ( CI 95% 68 fewer — 17 fewer ) Moderate Due to ongoing recruitment in a large RCT Baricitinib probably reduces mortality. Mechanical ventilation Odds ratio 0.8 (CI 95% 0.52 — 1.19) Based on data from 2434 participants in 2 studies. (Randomized controlled) 116 per 1000 Difference: 95 per 1000 21 fewer per 1000 ( CI 95% 52 fewer — 19 more ) Low Due to very serious imprecision 1 Baricitinib may reduce mechanical ventilation. Adverse effects leading to drug discontinuation Based on data from 1611 participants in 2 studies. (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 0 more — 28 more ) Moderate Due to serious imprecision 2 Baricitinib probably results in little or no increase in serious adverse effects. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 12.8 days (Median) Difference: 11.4 days (Mean) MD 1.4 fewer ( CI 95% 2.4 fewer — 0.4 fewer ) High Baricitinib reduces duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 54 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: very serious. Credible interval includes an important decrease and increase in mechanical ventilation. 2. Imprecision: serious. The credible interval includes an important increase in adverse effects. 3. Imprecision: serious. The credible interval includes no important difference. 4. Imprecision: very serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 14.7 days (Median) Difference: 11.5 days (Mean) MD 3.2 fewer ( CI 95% 5.9 fewer — 0.5 fewer ) Moderate Due to serious imprecision 3 Baricitinib probably reduces duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 9.9 days (Median) Difference: 8.9 days (Mean) MD 1 fewer ( CI 95% 2.9 fewer — 1.1 more ) Low Due to very serious imprecision 4 Baricitinib may reduce time to clinical stability. Clinical Question/ PICO Population: Patients with severe and critical COVID-19 Intervention: Baricitinib Comparator: Interleukin-6 receptor blockers Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.77 (CI 95% 0.53 — 1.1) Based on data from 2659 participants in 3 studies. (Randomized controlled) 118 per 1000 Difference: 96 per 1000 22 fewer per 1000 ( CI 95% 52 fewer — 9 more ) Low Due to serious imprecision and ongoing recruitment in a large RCT 1 Baricitinib may reduce mortality. Mechanical ventilation Odds ratio 1.01 (CI 95% 0.61 — 1.6) Based on data from 2434 participants in 2 studies. (Randomized controlled) 94 per 1000 Difference: 96 per 1000 2 more per 1000 ( CI 95% 38 fewer — 44 more ) Low Due to very serious imprecision 2 There may be little or no difference on mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 55 of 142 Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. The credible interval includes no important difference. 2. Risk of bias: no serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: very serious. The credible interval includes important benefit and important harm. 3. Imprecision: serious. The credible interval includes small but important harm. 4. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Inconsistency: serious. The trials that studied interleukin-6 receptor blockers had discrepant results: some increased length of stay, others reduced length of stay. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. The credible interval includes no important difference. 6. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Adverse effects leading to drug discontinuation Based on data from 2309 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 1 per 1000 1 more per 1000 ( CI 95% 11 fewer — 15 more ) Moderate Due to serious imprecision 3 There is probably little to no difference in adverse effects leading to discontinuation. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 8.1 days (Median) Difference: 11.2 days (Mean) MD 3.1 more ( CI 95% 3.8 fewer — 9.9 more ) Very low Due to serious risk of bias, serious inconsistency, and very serious imprecision 4 The impact on hospital length of stay is very uncertain. Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 13.8 days (Median) Difference: 11.6 days (Mean) MD 2.2 fewer ( CI 95% 5.3 fewer — 0.7 fewer ) Low Due to serious risk of bias and imprecision 5 Baricitinib may reduce duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 8.4 days (Median) Difference: 8.9 days (Mean) MD 0.5 more ( CI 95% 2.3 fewer — 3.2 more ) Low Due to serious risk of bias and imprecision 6 There may not be an important impact on time to clinical stability. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 56 of 142 Ruxolitinib and tofacitinib, for patients with severe or critical COVID-19 Practical Info Route, dosage and duration: We refer to the table of trial characteristics (ruxolitinib and tofacitinib) to guide the administration of these agents, in the absence of other available information. Timing: Ruxolitinib or tofacitinib (like IL-6 receptor blockers) should be initiated with systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. Evidence To Decision Conditional recommendation against We suggest not to use ruxolitinib or tofacitinib (conditional recommendation against). • Clinicians should consider using these drugs only if neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) are available. • The GDG emphasized the need for more trial evidence to better inform the recommendations. The effects of ruxolitinib or tofacitinib on mortality, need for mechanical ventilation and hospital length of stay remain uncertain. Tofacinib may increase adverse events leading to drug discontinuation. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no evidence of a subgroup effect on relative risk in younger (< 70 years) versus older patients; those receiving and not receiving corticosteroids; those with severe versus critical COVID-19; and those receiving and not receiving remdesivir. Benefits and harms Due to serious imprecision due to small cohorts (ruxolitinib: two RCTs, 475 patients; tofacitinib: one RCT, 289 patients) with few events and serious indirectness (pertaining to RCTs for ruxolitinib, most patients did not receive corticosteroids), certainty of evidence was rated as low or very low for all prioritized outcomes for both drugs. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that, given the low or very low certainty evidence on mortality and the other prioritized benefit outcomes and the remaining possibility of serious adverse effects, the majority of well-informed patients would not want to receive ruxolitinib or tofacitinib. The GDG anticipated, however, that because benefit has not been excluded, and because a class effect of JAK inhibitors might exist (such that baricitinib provides indirect evidence of benefit for the other JAK inhibitors), a minority of well-informed patients would choose to receive one or other drug in circumstances in which neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) were available. Values and preferences Resource implications, equity and human rights The GDG noted that, given the recommendation against use of ruxolitinib or tofacitinib, efforts to ensure access to drugs should focus on those that are currently recommended. Acceptability and feasibility As ruxolitinib and tofacitinib are administered orally twice daily, this treatment should be easy to accept for hospitalized patients with severe and critical COVID-19. In patients unable to swallow whole tablets, they can be dispersed in water to take orally or via nasogastric tube (see Practical info). Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 57 of 142 Justification When moving from evidence to the conditional recommendation not to use ruxolitinib or tofacitinib in patients with severe or critical COVID-19, the GDG emphasized the low to very low certainty evidence for mortality, duration of mechanical ventilation and possible increase in serious adverse events (particularly for tofacitinib). The GDG emphasized the need for more trial evidence to better inform the recommendations; this is anticipated through ongoing trials for these JAK inhibitors. Applicability None of the included RCTs enrolled children; therefore, the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regards to the administration of ruxolitinib or toficitinib to pregnant or lactating women. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Ruxolitinib Comparator: Standard care Summary Evidence summary The LNMA on ruxolitinib was informed by two RCTs that enrolled 475 patients across non-severe, severe and critical illness subgroups (65)(66). Both RCTs were registered, one was published in a peer-reviewed journal, and one was a trial registration only. Both RCTs enrolled patients in in-patient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with severe and critical COVID-19, the GRADE Summary of Findings tables for ruxolitinib shows the relative and absolute effects compared with usual care for the outcomes of interest, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significant relative subgroup effects were found. Please see the Summary accompanying the recommendation for baricitinib for more details. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ruxolitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.87 (CI 95% 0.27 — 2.85) Based on data from 472 participants in 2 studies. (Randomized controlled) 130 per 1000 Difference: 115 per 1000 15 fewer per 1000 ( CI 95% 91 fewer — 169 more ) Very low Due to serious indirectness and very serious imprecision 1 The effect of ruxolitinib is very uncertain. Mechanical ventilation Odds ratio 0.87 (CI 95% 0.36 — 2.04) Based on data from 472 participants in 2 studies. (Randomized controlled) 116 per 1000 Difference: 108 per 1000 8 fewer per 1000 ( CI 95% 71 fewer — 94 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect of ruxolitinib is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 58 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ruxolitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit. 2. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit. 3. Imprecision: very serious. There was only one event in the single trial that reported this outcome, of 424 patients enrolled in the study. 4. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Indirectness: serious. Imprecision: very serious. 6. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of Adverse effects leading to drug discontinuation Based on data from 484 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 5 per 1000 2 more per 1000 ( CI 95% 0 more — 15 more ) Low Due to very serious imprecision 3 Ruxolitinib may not cause an important increase in adverse effects leading to drug discontinuation. Hospital length of stay Lower better Based on data from 472 participants in 2 studies. (Randomized controlled) 12.8 days (Median) Difference: 11.4 days (Mean) MD 0.1 more ( CI 95% 2.1 fewer — 2.4 more ) Very low Due to serious indirectness and very serious imprecision 4 The impact of ruxolitinib on hospital length of stay is very uncertain. Duration of mechanical ventilation Based on data from 3 participants in 1 study. (Randomized controlled) 14.7 days (Median) Very low Insufficient data 5 The effect of ruxolitinib on mechanical ventilation is unknown. Time to clinical stability Lower better Based on data from 472 participants in 2 studies. (Randomized controlled) 9.9 days (Median) Difference: 9.8 days (Mean) MD 0.1 fewer ( CI 95% 2.5 fewer — 2.8 more ) Very low Due to serious indirectness and very serious imprecision 6 The impact of ruxolitinib on time to clinical stability is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 59 of 142 corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Tofacitinib Comparator: Standard care Summary Evidence summary The LNMA for tofacitinib was informed by one RCT that enrolled 289 patients across non-severe, severe and critical illness subgroups (67). The trial was registered and published in a peer-reviewed journal; it excluded children and pregnant women. Table shows characteristics of the RCT. For patients with severe or critical COVID-19, the GRADE Summary of Findings table for tofacitinib shows the relative and absolute effects compared with standard care for the outcomes of interest, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significant relative subgroup effects were found. Please see the Summary accompanying the recommendation for baricitinib for more details. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Tofacitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.47 (CI 95% 0.11 — 1.63) Based on data from 289 participants in 1 study. (Randomized controlled) 130 per 1000 Difference: 78 per 1000 52 fewer per 1000 ( CI 95% 113 fewer — 69 more ) Very low Due to extremely serious imprecision 1 The effect of tofacitinib is uncertain. Mechanical ventilation Odds ratio 0.5 (CI 95% 0.17 — 1.37) Based on data from 289 participants in 1 study. (Randomized controlled) 116 per 1000 Difference: 68 per 1000 48 fewer per 1000 ( CI 95% 94 fewer — 35 more ) Very low Due to extremely serious imprecision 2 The effect of tofacitinib is uncertain. Adverse effects leading to drug discontinuation Based on data from 284 participants in 1 study. (Randomized controlled) 0 per 1000 77 per 1000 Low Due to very serious imprecision 3 Tofacitinib may increase adverse effects leading to drug discontinuation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 60 of 142 6.7.1 Mechanism of action Type I and type II cytokine receptors are a family of receptors employed by over 50 interleukins, interferons, colony stimulating factors, and hormones (68). The intracellular signalling triggered by these receptors is mediated by Janus kinases (JAKs), a small family of kinases including JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Type I cytokines include IL-2, IFN-γ, IL-12, and TNFb, and type II cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. JAK inhibitors are a class of drugs which inhibit intracellular signalling through multifactorial effects on cytokine signalling. As a consequence, they interfere with many cellular responses, including antiviral responses, angiotensin-converting enzyme 2 (ACE2) expression, T cell function and differentiation, and macrophage activation (68). Baricitinib, ruxolitinib, and tofacitinib are three of at least nine JAK inhibitors. These three drugs are all generally considered to be non-specific JAK inhibitors, but differences in the specificity and potency for different JAKs are evident. Baricitinib has been described as a JAK1/JAK2 inhibitor, ruxolitinib as JAK1/JAK2 > TYK2, and tofacitinib as JAK3/JAK1 > JAK2/TYK2; other differences have also been previously described (68)(69)(70). Studies evaluating JAK inhibitors for the treatment of COVID-19 have been conducted at doses that are as high or higher than those approved for other indications, such as rheumatoid arthritis, myelofibrosis, and ulcerative colitis. Therefore, plausibility is contingent upon the role of cytokine signalling in COVID-19, and not on whether the pharmacokinetics at the studied dose is Outcome Timeframe Study results and measurements Comparator Standard care Intervention Tofacitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: extremely serious. The credible interval includes important benefit and important harm. There were only 12 events total. 2. Imprecision: extremely serious. Credible interval includes important benefit and important harm. There were only 18 events in total. 3. Imprecision: very serious. Very few events: only 21 in total (16/142 in tofacitinib arm and 5/142 in placebo arm). 4. Imprecision: very serious. Credible interval includes no important difference. ( CI 95% 17 more — 138 more ) Hospital length of stay Lower better Based on data from 289 participants in 1 study. (Randomized controlled) 12.8 days (Median) Difference: 11.7 days (Mean) MD 1.1 fewer ( CI 95% 2.8 fewer — 0.6 more ) Low Due to very serious imprecision 4 Tofacitinib may reduce duration of hospitalization. Duration of mechanical ventilation 14.7 days (Median) Very low No data The impact of tofacitinib on duration of mechanical ventilation is unknown. Time to clinical stability 9.9 days (Median) Very low No data The effect of tofacitinib on time to clinical stability is unknown. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 61 of 142 Difference: 77 more per 1000 sufficient to inhibit the target proteins. There are notable differences in the approved doses, schedules, pharmacokinetics, contraindications, and indications of these drugs for other indications. Collectively, these differences limit the confidence to consider a class-wide recommendation with currently available data. 6.8 Sotrovimab (published 14 January 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in a summary of practical issues. Here follows a brief summary of key points. • The authorized dose for sotrovimab is one single intravenous infusion of 500 mg over 30 minutes, administered as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset. • Sotrovimab is available as a concentrated solution, and must be diluted prior to administration. • Patients should be clinically monitored patients during the infusion, and observed for at least 1 hour after the infusion is completed. Evidence To Decision Info Box Recommendations concerning sotrovimab for patients with non-severe COVID-19 were published on 14 January 2022 as the eighth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of one RCT for non-severe illness, as per the LNMA on antibody and cellular therapies (2). No changes were made to the sotrovimab recommendation in this eleventh version of the guideline. The GDG is currently assessing to what extent the increasingly predominant Omicron BA.2 variant is substantially reducing the clinical efficacy of sotrovimab, at this stage demonstrated through pre-clinical in-vitro data (see Mechanism of action). The GDG also notes that several therapeutic alternatives are available for patients with non-severe COVID-19 at highest risk of hospitalization (see Section 6.1 and remarks below the recommendation). Conditional recommendation for We suggest treatment with sotrovimab (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk of being hospitalized. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies, including sotrovimab and casirivimab-imdevimab. • The GDG concluded that nirmatrelvir-ritonavir may represent a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • The Omicron BA.2 variant may substantially reduce clinical efficacy of sotrovimab; the GDG is currently assessing this issue. • Patients with severe or critical COVID-19: based on current evidence, the benefit of sotrovimab in seronegative patients with severe or critical COVID-19 (see casirivimab-imdevimab recommendation in Section 6.10) remains unclear. This means that careful clinical judgment needs to be applied if casirivimab-imdevimab is unavailable and sotrovimab is considered. Benefits and harms In patients with non-severe illness, sotrovimab probably reduces hospitalization, with little or no impact on infusion reactions, with no data on time to clinical improvement. Sotrovimab probably has little or no impact on mortality and on mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 62 of 142 Justification A combination of the evidence, values and preferences, and feasibility contributed to the conditional recommendation for the use of sotrovimab only in individuals with non-severe COVID-19 at highest risk of hospitalization. Typical characteristics of people at highest risk include those who are unvaccinated, older people, or those with immunodeficiencies and/or chronic investigators. The evidence summary was informed by one RCT with 1057 patients (COMET-ICE), included in the LNMA (74). This trial provides evidence of moderate certainty for reduced hospitalization (due to serious imprecision), high certainty for absence of infusion reactions, moderate certainty (due to serious indirectness) for no or small difference in mortality and low certainty (due to serious indirectness and imprecision) for no or small difference in mechanical ventilation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence. In addition, the GDG felt that there was some indirectness because of the possible emergence of variants for which the effectiveness of currently available monoclonal antibodies may be reduced. When rating precision, the GDG considered the estimates of the absolute risks. Accordingly, in the context of very low event rates (e.g. very low risk of death among patients with non-severe illness), the GDG did not rate down for imprecision despite relative risks with wide confidence intervals. Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline sotrovimab, and only those at highest risk (e.g. unvaccinated, older, or immunosuppressed) would choose to receive treatment. In the absence of research evidence, in a previous survey (see recommendation for casirivimab-imdevimab), the GDG expressed the view that most patients with a risk of hospitalization above 10%, and thus an absolute risk reduction of approximately 6%, would choose to receive treatment, whereas most of those below that risk level would decline treatment. These thresholds were also used here. Values and preferences Acceptability and feasibility The GDG noted that sotrovimab is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This further supports the guidance that sotrovimab be reserved for those at highest risk of hospitalization. Additional challenges include the requirement for intravenous administration to patients who would normally be treated at home. Specialized clinics may be required to ensure safe and effective administration of sotrovimab. For the intervention to achieve substantial use, healthcare systems will have to address these challenges. Given the cost and availability of sotrovimab, and the obstacles to ensuring access in LMICs may prove formidable. For example, those with socioeconomic disadvantages tend to have less frequent access to services in the first 5 days of symptoms and then less access to the interventions. Thus, the panel’s suggestion that patients at highest risk receive the intervention may exacerbate health inequity. On the other hand, given the demonstrated benefits for patients and the still low vaccine coverage in some LMICs and low-income countries (LICs), sotrovimab may be a useful tool to reduce hospitalization from COVID-19 in unvaccinated populations. The recommendations should also provide a stimulus to engage all possible mechanisms to improve global access to the intervention. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. On 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which includes sotrovimab. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 63 of 142 The planned subgroup analyses could not be performed in the absence of subgroup data reported publicly or provided by diseases (e.g. diabetes). Although there is moderate certainty evidence of a substantial relative risk reduction in hospitalization, only a minority of patients who are at highest risk are likely to achieve sufficient benefit to compensate for the risks, and other limitations and disadvantages of this therapy. These include a lack of reliable tools to identify high-risk patients, delivering a parenteral therapy to patients who are typically cared for in the community, and limited availability of the drug. The role of sotrovimab and casirivimab-imdevimab Another combination of monoclonal antibodies, casirivimab-imdevimab, is also conditionally recommended in patients with non-severe COVID-19 at highest risk of hospitalization. The GDG advised that clinicians do not administer the drugs together, given an absence of evidence of incremental benefit of the drugs when given together, and the low likelihood of incremental benefit mechanistically. The GDG then considered how to choose between the two drugs. No trials provide head-to-head comparisons. With Alpha and Delta variants, there may be little or no difference in the agents’ impact on critical outcomes, according to an indirect comparison from the LNMA (see GRADE Summary of Findings table in Research evidence). Now and in the future, the choice of monoclonal antibodies will depend on emerging information regarding effectiveness with different variants and their availability, as well as clinical and contextual factors. Of note, the RCTs included in the LNMA were conducted before the emergence of the Omicron variant. Following the publication of a previous conditional recommendation for casirivimab-imdevimab, pre-clinical evidence has emerged suggesting that this monoclonal antibody combination lacks neutralization activity against the Omicron variant in vitro (71). Recent pre-clinical data demonstrate that sotrovimab has greatly reduced neutralization activity against the increasingly predominant Omicron BA.2 variant (see Mechanism of action). In the absence of clinical evidence, the effects on the efficacy of sotrovimab remains unclear and is currently being assessed by the GDG. Applicability Children and pregnant women: The included RCT enrolled only non-pregnant adults; therefore, the applicability to children and pregnant women remains uncertain. The GDG had no reason to believe that children or pregnant women with COVID-19 would respond differently to treatment with sotrovimab. However, for children, as the risk of hospitalization is generally extremely low, the GDG inferred that, in the absence of immunosuppression or another significant risk factor, children should not receive the intervention. Severe and critical COVID-19: An RCT randomized 546 adults hospitalized with COVID-19 to two neutralizing monoclonal antibody therapies (sotrovimab and BRII-196 plus BRII-198) or placebo (73). The results did not demonstrate benefits from these antibodies therapies, including a subgroup analysis on patients with seropositive versus seronegative status.Although the role of sotrovimab in severe and critical COVID-19 is not supported by the new trial, it was not assessed by the GDG, as they focused on patients with non-severe COVID-19 where evidence was available at the time of recommendation development; this trial, and any other new evidence that is publicly available, will be fully considered by the GDG for future recommendations for sotrovimab. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Sotrovimab Comparator: Standard care Summary The LNMA for sotrovimab was informed by one RCT (COMET-ICE) that randomized 1057 non-hospitalized patients with symptomatic COVID-19 (≤ 5 days after the onset of symptoms) and at least one risk factor for disease progression. Of the 1057 randomized patients, the LNMA team had access to data for 1044 patients. Included patients were randomized to receive a single infusion of sotrovimab at a dose of 500 mg, or placebo. Median age of patients was 53 years; 46% were male. Median duration of follow-up in the intention-to-treat population was 72 days. Vaccinated patients were excluded from the trial (74). The GRADE Summary of Findings table shows the relative and absolute effects of sotrovimab compared with standard care (placebo) for the outcomes of interest, with certainty ratings. Subgroup analysis Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 64 of 142 Four pre-specified subgroup analyses were requested by the GDG: 1. Age: children versus adults (< 70 years) versus older adults (≥ 70 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Time of symptom onset. 4. Serological status. No data were available in the trial to conduct these analyses. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.11 (CI 95% 0 — 2.6) Based on data from 1044 participants in 1 study. (Randomized controlled) 6 per 1000 Difference: 1 per 1000 5 fewer per 1000 ( CI 95% 6 fewer — 9 more ) Moderate Due to serious indirectness and some concerns with imprecision 1 Sotrovimab probably has little or no impact on mortality. Mechanical ventilation Odds ratio 0.11 (CI 95% 0 — 2.6) Based on data from 1044 participants in 1 study. (Randomized controlled) 8 per 1000 Difference: 1 per 1000 7 fewer per 1000 ( CI 95% 8 fewer — 13 more ) Low Due to serious indirectness and serious imprecision 2 Sotrovimab may have little or no impact on mechanical ventilation. Admission to hospital Risk in trials Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 35 per 1000 Difference: 7 per 1000 28 fewer per 1000 ( CI 95% 33 fewer — 17 fewer ) Moderate Due to serious imprecision 3 Sotrovimab probably reduces admission to hospital. Admission to hospital Higher risk Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 60 per 1000 Difference: 12 per 1000 48 fewer per 1000 ( CI 95% 56 fewer — 28 fewer ) Moderate Due to serious imprecision 4 Sotrovimab probably reduces admission to hospital. Admission to hospital Highest risk Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 100 per 1000 Difference: 21 per 1000 79 fewer per 1000 ( CI 95% 93 fewer — 46 fewer ) Moderate Due to serious imprecision 5 Sotrovimab probably reduces admission to hospital. Infusion reactions Based on data from 1044 participants in 1 0 per 1000 0 per 1000 High Sotrovimab results in little or no increase in infusion reactions. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 65 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, sotrovimab may have an important impact on mortality. Imprecision: no serious. There were only four deaths (all in the placebo group) in the single trial that studied sotrovimab. 2. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, sotrovimab may have an important impact on mechanical ventilation. Imprecision: serious. Very few events – only four patients received invasive mechanical ventilation in the single trial (all in the placebo group). 3. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. 4. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. 5. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. studies. (Randomized controlled) Difference: 0 fewer per 1000 ( CI 95% 13 fewer — 13 more ) Time to symptom resolution No data The effect of sotrovimab is unknown. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Sotrovimab Comparator: Casirivimab-imdevimab Outcome Timeframe Study results and measurements Comparator Casirivimab- imdevimab Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation Odds ratio 0 (CI 95% 0 — 0.01) (Randomized controlled) 2 per 1000 Difference: 0 per 1000 2 fewer per 1000 ( CI 95% 2 fewer — 2 fewer ) Moderate Due to serious indirectness and some concerns with imprecision 1 There is probably little or no difference on mechanical ventilation. Mortality Odds ratio 0.53 (CI 95% 0.09 — 2.12) (Randomized controlled) 3 per 1000 2 per 1000 Moderate Due to serious indirectness and some concerns with imprecision 2 There is probably little or no difference on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 66 of 142 Outcome Timeframe Study results and measurements Comparator Casirivimab- imdevimab Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mechanical ventilation will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, whether there is an important difference in mechanical ventilation is uncertain. Imprecision: no serious. Very few events – only two patients received invasive mechanical ventilation in the single trial (both in the placebo group). 2. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, the effect on mortality is uncertain. Imprecision: no serious. There was only one death (in the placebo group) in the single trial that studied sotrovimab. 3. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. 4. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. 5. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. ( CI 95% 3 fewer — 3 more ) Admission to hospital Higher risk Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 18 per 1000 Difference: 12 per 1000 6 fewer per 1000 ( CI 95% 14 fewer — 17 more ) Moderate Due to serious indirectness and some concerns with imprecision 3 There is probably little or no difference in hospitalization. Infusion reactions 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 13 fewer — 13 more ) High There is little or no difference in infusion reactions. Admission to hospital Highest risk Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 31 per 1000 Difference: 21 per 1000 10 fewer per 1000 ( CI 95% 24 fewer — 28 more ) Moderate Due to serious indirectness and some concerns with imprecision 4 There is probably little or no difference in hospitalization. Admission to hospital Risk in trials Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 10 per 1000 Difference: 7 per 1000 3 fewer per 1000 ( CI 95% 8 fewer — 10 more ) Moderate Due to serious indirectness and some concerns with imprecision 5 There is probably little or no difference in hospitalization. Time to clinical improvement No data The effect of sotrovimab is unknown. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 67 of 142 Difference: 1 fewer per 1000 6.8.1 Mechanism of action Sotrovimab (VIR-7831; GSK4182136) is a single human monoclonal antibody that binds to a conserved epitope of the SARS- CoV-2 spike protein, preventing the virus from entering cells. Sotrovimab is an Fc-engineered IgG monoclonal antibody that is expected to have a longer half-life than unmodified IgG monoclonal antibodies, but there are no publicly available data regarding its half-life in humans. No published pre-clinical or human pharmacokinetic data were available for review; assessment was therefore based upon public regulatory information and the GSK Product Monograph (75). Antiviral activity in a Syrian Golden hamster model of SARS-CoV-2 infection was demonstrated at 5 mg/kg IP but with a version of the antibody that was not Fc-engineered (75). Neutralization of SARS-CoV-2 (USA WA1/2020) was achieved in Vero E6 cells with an EC90 value of 0.19 µg/mL (76). Sotrovimab serum concentrations in COMET-ICE (single 500 mg IV infusion) provided geometric mean Cmax (at the end of a 1 hr IV infusion) of 117.6 µg/mL (N=129, CV% 40) and a geometric mean Day 29 serum concentration of 24.5 µg/mL (76). Population mean serum concentrations are therefore expected to be 129-fold higher after 29 days than the concentrations needed in vitro to neutralize the original strain of SARS-CoV-2. A review manuscript with Vir Biotechnology authors indicates less than 10-fold loss of neutralization for sotrovimab for all tested variants of concern, which did not at the time include Omicron (77). Information in the FDA Emergency Use Authorization also state “no change” in activity of sotrovimab against Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta (including with K417N), Lambda and Mu in pseudo-typed virus-like particle neutralization assays (76). Sotrovimab has been reported to retain activity against BA.1 Omicron in pseudovirus assays but with higher concentrations being required for neutralization compared with the wild-type virus (72). Several reports have indicated that the neutralization of the BA.2 sub-lineage of Omicron is more severely impacted than it is for BA.1 (79)(78)(https://www.biorxiv.org/ content/10.1101/2021.03.09.434607v10). A better understanding of the pharmacokinetic-pharmacodynamic relationship will be need to ascertain the consequences of these reduced activities for efficacy of sotrovimab. An E340A amino acid substitution in the conserved epitope of the spike protein emerged rapidly under a selective pressure with sotrovimab in cell culture, and subsequent characterization using a pseudovirus assay resulted in a > 100-fold reduction in susceptibility to sotrovimab (76). Sixteen other substitutions introduced into the epitope were also described as reducing neutralization by sotrovimab by between 5.4 and > 297-fold (76). Therefore, resistance to sotrovimab can emerge under experimental conditions. Additionally, 4 of the first 1000 consecutive patients treated with sotrovimab during a Delta wave in Australia are reported to have developed E340 mutations in their viral sequences, and remained culture positive for 12–24 days after dosing (80). 6.9 Convalescent plasma (published 7 December 2021) For patients with non-severe COVID-19 Practical Info The GDG made a strong recommendation against using convalescent plasma for the treatment of patients with non-severe COVID-19 and a recommendation against using convalescent plasma in those with severe or critical COVID-19 outside the context of a clinical trial. Given this, we will not go into detail regarding the many practical issues related to convalescent plasma Info Box Recommendations concerning convalescent plasma for patients with non-severe, severe and critical COVID-19 were published on 7 December 2021 as the seventh version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of 16 RCTs across disease severities, as per the LNMA on antibody and cellular therapies (2). No changes were made to the convalescent plasma recommendations in this eleventh version of the guideline. Strong recommendation against We recommend against treatment with convalescent plasma (strong recommendation against). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 68 of 142 including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution of plasma, and infusion of convalescent plasma into recipients. Evidence To Decision Justification A combination of the evidence, values and preferences, and feasibility contributed to the strong recommendation against convalescent plasma in patients with non-severe COVID-19. Most importantly, given there was no benefit demonstrated in any of the critical or important outcomes for either non-severe or severe or critical COVID-19, the GDG did not see any justification for the resources (including time and cost) that would be associated with administration of convalescent plasma. The recommendation also took into account possible associated harms (although not demonstrated in the evidence summary, there is always a potential for harms with blood product transfusion), the low baseline risk of mortality, mechanical ventilation, and hospitalization in non-severe illness, and feasibility challenges with the administration of convalescent plasma. Titres Titres of neutralizing antibodies varied substantially between included trials, with over half of the trials not reporting or considering recipient titres at all. In fact, the largest trial (RECOVERY) did not report on donor antibody titres at all. Even when titres were reported, the method for testing and the volume of plasma infused varied. This made it impossible to provide any analysis based on donor titre levels or assess for credible subgroup effects. In non-severe patients, convalescent plasma does not result in an important impact on mortality. Convalescent plasma probably does not impact mechanical ventilation. There were no data evaluating the risk of hospitalization with convalescent plasma and therefore the impact is very uncertain. Convalescent plasma probably does not result in important increases in risks of transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), or allergic reactions. Benefits and harms The certainty in mortality was high, whereas mechanical ventilation was moderate due to serious risk of bias. Certainty was rated as moderate for TRALI and TACO due to serious risk of bias, and for allergic reactions due to concerns regarding risk of bias and imprecision. Certainty of the Evidence The GDG inferred that, in addition to the agreed upon values and preferences (see Section 7), almost all well-informed patients would choose against receiving convalescent plasma based on available evidence regarding relative benefits and harms. From a population perspective, feasibility, acceptability, equity and cost are other important elements to take into account (see Section 7). For patients with non-severe illness, the GDG considered that resource and feasibility issues may be amplified in the outpatient setting, and mobilizing the use of convalescent plasma on a large scale would likely be of questionable feasibility. Values and preferences Acceptability and feasibility The GDG noted that convalescent plasma use is associated with significant resource requirements including identification of potential donors, testing of donors to ensure adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of plasma, transportation of plasma to recipient location, and administration of plasma. These resources and feasibility issues are compounded for those with non-severe disease who are most often outpatients. Also, this process is costly and time-consuming. Given the number of patients with non-severe disease and the low event rate in this subgroup of patients, mobilizing the use of convalescent plasma on a large scale would be of questionable feasibility. Although blood transfusion is acceptable to most, there is a subset of the population that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions related to blood product transfusion. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 69 of 142 Applicability The applicability of this recommendation to children or pregnant women is currently uncertain, as the included RCTs enrolled non-pregnant adults. The GDG had no reason to think that children with COVID-19 would respond any differently to treatment with convalescent plasma. However, the risk of hospitalization in children is generally extremely low and the GDG inferred that in the absence of immunosuppression or another significant risk factor children should not receive the intervention. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Convalescent plasma Comparator: Standard care Summary Evidence summary The LNMA on convalescent plasma included 16 RCTs that enrolled 16 236 patients across non-severe, severe, and critical illness subgroups. All RCTs were registered, and 80% were published in peer-reviewed journals; 20% were pre- prints. 99% of participants were enrolled from in-patient settings; of them, 15% were admitted to the intensive care unit (ICU). 1% of patients were enrolled from outpatient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs, of which two trials used comparisons to plasma as placebo and were not included in the evidence summaries. We are aware of two additional published RCTs comparing convalescent plasma to standard care or placebo (81)(82). These trials were not incorporated in the latest analysis presented to the GDG, based on which recommendations were made. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of convalescent plasma compared with usual care for the outcomes of interest,with certainty ratings. This evidence summary was informed by the LNMA (2) pooling data from 1602 patients in 4 RCTs for the outcome of mortality and less data available for other outcomes, except for allergic reactions (8 RCTs, 243 patients). See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis We pre-specified the following subgroup analyses of interest: 1. Age: younger adults (< 70 years) versus older adults (> 70 years). 2. Severity of illness (at time of treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma. The subgroup analyses were performed on patients across all disease severities. The majority of subgroups did not have sufficient data across outcomes of interest to pursue subgroup analyses. Of those that did, we found no significant subgroup effects for severity of illness (p=0.80) and age (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical ventilation. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mortality closest to 90 days Odds ratio 0.83 (CI 95% 0.43 — 1.46) Based on data from 1602 participants in 4 studies. 1 (Randomized controlled) 3 per 1000 Difference: 2 per 1000 1 fewer per 1000 ( CI 95% 2 fewer — 1 more ) High 2 Convalescent plasma does not result in an important impact on mortality. Mechanical ventilation closest to 90 days Odds ratio 0.71 (CI 95% 0.18 — 1.77) Based on data from 705 6 per 1000 4 per 1000 Moderate Due to serious risk of bias 4 Convalescent plasma probably does not impact mechanical Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 70 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [87], [83], [84], [86], 2. Risk of bias: no serious. The GDG did not rate down for risk of bias due to lack of blinding. . 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [83], [84], [87], 4. Risk of bias: serious. Imprecision: no serious. The GDG did not rate down for imprecision, because the credible interval excludes an important benefit and important harm. 5. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [88], [84], [89], [85], 6. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect and baseline risk is very low. 7. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], [85], [83], [88], 8. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is very low. 9. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [92], [88], [86], [83], [91], [85], [89], [90], 10. Risk of bias: serious. 2 trials (491 patients; 3% of total) were at low risk of bias vs. 6 trials (14 910 patients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some concern regarding allergic reactions, though acknowledges that the baseline risk is low. participants in 3 studies. 3 (Randomized controlled) Difference: 2 fewer per 1000 ( CI 95% 5 fewer — 5 more ) ventilation. Transfusion- related acute lung injury (TRALI) within 28 days Based on data from 1365 participants in 4 studies. 5 (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 5 fewer — 6 more ) Moderate Due to serious risk of bias 6 Convalescent plasma probably does not result in an important increase in TRALI. Transfusion- associated circulatory overload (TACO) within 28 days Based on data from 1442 participants in 4 studies. 7 (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 3 fewer — 12 more ) Moderate Due to serious risk of bias 8 Convalescent plasma probably does not result in an important increase in TACO. Allergic reactions within 28 days Odds ratio 3.25 (CI 95% 1.27 — 9.3) Based on data from 15 243 participants in 8 studies. 9 (Randomized controlled) 3 per 1000 Difference: 10 per 1000 7 more per 1000 ( CI 95% 1 more — 24 more ) Low Due to concerns with risk of bias and imprecision 10 Convalescent plasma probably does not result in an important increase in allergic reactions. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 71 of 142 For patients with severe or critical COVID-19 Practical Info The GDG made a recommendation against using convalescent plasma in those with severe or critical COVID-19 outside the context of a clinical trial and a strong recommendation against using convalescent plasma for treatment of patients with non- severe COVID-19. Given this, we will not go into detail regarding the many practical issues related to convalescent plasma including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution of plasma, and infusion of convalescent plasma into recipients. Evidence To Decision Justification After substantial discussion, the GDG decided to make a recommendation against convalescent plasma in patients with severe or critical COVID-19, except in the context of clinical trials. Given the low certainty evidence suggesting a small or no effect on Only in research settings We recommend not to use convalescent plasma for treatment of COVID-19, except in the context of a clinical trial (recommended only in research settings). In severe or critical patients, convalescent plasma may not result in an important impact on mortality, mechanical ventilation, time to symptom improvement, length of hospital stay or ventilator-free days. Convalescent plasma probably does not result in important increases in risks of TRALI, TACO or allergic reactions. However, there is always potential for harms with blood product transfusion although not demonstrated in the evidence summary. Benefits and harms The certainty in mortality was low due to concerns with indirectness, risk of bias and imprecision. The GDG rated down certainty to low for mechanical ventilation, length of hospital stay and ventilator-free days for serious risk of bias and serious imprecision, and to low for time to symptom improvement due to very serious imprecision. Certainty was rated as moderate for TRALI and TACO due to serious risk of bias, and for allergic reactions due to concerns regarding risk of bias and imprecision. Certainty of the Evidence The GDG inferred that, in addition to the agreed upon values and preferences (see Section 7), almost all well-informed patients would choose against receiving convalescent plasma based on available evidence regarding relative benefits and harms. From a population perspective, feasibility, acceptability, equity and cost are other important elements to take into account (see Section 7). Values and preferences Acceptability and feasibility The GDG noted that convalescent plasma use is associated with significant resource requirements including identification of potential donors, testing of donors to ensure adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of plasma, transportation of plasma to recipient location, and administration of plasma. Also, this process is costly and time-consuming. Although blood transfusion is acceptable to most, there is a subset of the population that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions related to blood product transfusion. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 72 of 142 mortality, mechanical ventilation, and time to symptom improvement, with possible associate harms (although not demonstrated in the evidence summary, there is always a potential for harms with blood product transfusion) the panel agreed further research addressing these patient-important outcomes would be valuable. This research focus on severe or critical COVID-19 was also informed by the feasibility (patients are already hospitalized) and baseline risk of mortality and requiring life support interventions (higher in severe or critical COVID-19). The panel identified high titre products as the highest priority for future research as well as the need of reporting on donor titre and volume infused which can give an idea of dilution of titres in the recipient. Similarly, the panel identified seronegative COVID-19 patients as the highest priority for future convalescent plasma research. A recommendation to only use a drug in the setting of clinical trials is appropriate when there is low certainty evidence, and future research has a potential for reducing uncertainty about the effects of the intervention and for doing so at a reasonable cost. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Convalescent plasma Comparator: Standard care Summary Evidence summary for convalescent plasma Please see summary for patients with non-severe COVID-19 above. It provides details about the LNMA and 16 included trials across disease severities, as well as subgroup analyses that did not detect credible effects based on age, severity of illness, or dosage of convalescent plasma. The GRADE Summary of Findings table shows the relative and absolute effects of convalescent plasma compared with usual care for the outcomes of interest for patients with severe and critical COVID-19, with certainty ratings. This evidence summary was informed by the LNMA (2), pooling data from from 14 366 patients in 10 studies for the outcome of mortality, with less data available for other outcomes. Baseline risk estimates For severe and critical illness, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence (see Section 7). Subgroup analysis We pre-specified the following subgroup analyses of interest: 1. Age: younger adults (< 70 years) versus older adults (> 70 years). 2. Severity of illness (at time of treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma. The majority of subgroups did not have sufficient data across outcomes of interest to pursue subgroup analyses. Of those that did, we found no significant subgroup effects for severity of illness (p=0.80) and age (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical ventilation. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mortality closest to 90 days Odds ratio 0.92 (CI 95% 0.7 — 1.12) Based on data from 14 366 participants in 10 studies. 1 (Randomized controlled) 130 per 1000 Difference: 121 per 1000 9 fewer per 1000 ( CI 95% 35 fewer Very low Due to concerns with indirectness, risk of bias, and imprecision 2 Convalescent plasma may have a small or no effect on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 73 of 142 — 13 more ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation closest to 90 days Odds ratio 0.92 (CI 95% 0.46 — 1.68) Based on data from 623 participants in 5 studies. 3 (Randomized controlled) 86 per 1000 Difference: 80 per 1000 6 fewer per 1000 ( CI 95% 45 fewer — 50 more ) Low Due to serious risk of bias and serious imprecision 4 Convalescent plasma may not impact mechanical ventilation. Transfusion- related acute lung injury (TRALI) within 28 days Based on data from 1365 participants in 4 studies. 5 (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 5 fewer — 6 more ) Moderate Due to serious risk of bias 6 Convalescent plasma probably does not result in an important increase in TRALI. Transfusion- associated circulatory overload (TACO) within 28 days Based on data from 1442 participants in 4 studies. 7 (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 3 fewer — 12 more ) Moderate Due to serious risk of bias 8 Convalescent plasma probably does not result in an important increase in TACO. Allergic reactions within 28 days Odds ratio 3.25 (CI 95% 1.27 — 9.3) Based on data from 15 243 participants in 8 studies. 9 (Randomized controlled) 3 per 1000 Difference: 10 per 1000 7 more per 1000 ( CI 95% 1 more — 24 more ) Low Due to concerns with risk of bias and imprecision 10 Convalescent plasma probably does not result in an important increase in allergic reactions. Time to symptom improvement Lower better Based on data from 472 participants in 3 studies. 11 (Randomized controlled) 15 (Mean) Difference: 15 (Mean) MD 0 fewer ( CI 95% 10.4 fewer — 33.6 more ) Low Due to very serious imprecision 12 Convalescent plasma may not impact time to symptom improvement. Length of hospital stay Measured by: days Lower better Based on data from 1015 participants in 7 studies. 13 (Randomized controlled) 11.7 days (Mean) Difference: 11 days (Mean) MD 0.7 fewer ( CI 95% 2.3 fewer — 1 more ) Low Due to serious risk of bias and serious imprecision 14 Convalescent plasma may not impact length of hospital stay. Ventilator-free days Measured by: days High better 13.7 days (Mean) 13 days (Mean) Low Due to serious Convalescent plasma may not impact the Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 74 of 142 within 28 days 6.9.1 Mechanism of action The proposed primary mechanism of action for convalescent plasma involves the transfer of endogenously produced neutralizing antibodies present within the plasma from previously infected and recovered patients into patients with active infection (97). Therefore, the underlying plausibility for this mechanism of action depends upon whether sufficient antibody concentrations remain following the dilution from donor to recipient. As such, the neutralizing antibody titre within the donor plasma as well as the volume administered are likely to be important. Data generated in Syrian golden hamsters have demonstrated efficacy of convalescent plasma against SARS-CoV-2 at a titre of 1:2560, but not at a titre of 1:320, when given at a volume of 1 mL, which extrapolates based on average blood volume to a human dosing volume of 300 mL (98). At the extremes of the studies which have investigated convalescent plasma clinically and reported the dose in terms of neutralizing antibody titre and volume administered, administration of 200 mL would be expected to result in an average dilution of 25-fold whereas administration of 1000 mL would be expected to result in an average dilution of 5-fold from those Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], [93], [95], [92], [90], [88], [94], [86], [96], [91], 2. Risk of bias: serious. Indirectness: serious. Imprecision: serious. Credible intervals include both important benefit and important harm. 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [93], [89], [85], [92], [95], 4. Risk of bias: serious. Imprecision: serious. The GDG decided the credible intervals warranted downgrading only once for imprecision. 5. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [85], [89], [84], [88], 6. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is low. 7. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [88], [83], [89], [85], 8. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is low. 9. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [91], [85], [89], [83], [92], [88], [90], [86], 10. Risk of bias: serious. 2 trials (491 patients; 3% of total) were at low risk of bias vs. 6 trials (14 910 patients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some concern regarding allergic reactions, though acknowledges the baseline risk is low. 11. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], 12. Imprecision: very serious. 13. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [93], [88], [94], [95], [96], [92], [89], 14. Risk of bias: serious. All studies except one were not adequately blinded. Imprecision: serious. Credible interval does not exclude small but important benefit. 15. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [92], [88], [90], 16. Risk of bias: serious. Almost all patients were randomized to trials that were not blinded. Imprecision: serious. Credible interval does not exclude important benefit. Based on data from 2859 participants in 3 studies. 15 (Randomized controlled) Difference: MD 0.7 fewer ( CI 95% 1.8 fewer — 0.4 more ) risk of bias and serious imprecision 16 number of ventilator- free days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 75 of 142 titres present in the circulation of the donor themselves (assuming an average human blood volume of 5 L (99)). It should be further recognized that the concentrations (titre) of neutralizing antibodies present within convalescent plasma are highly variable between donors and that there are different methodologies available to measure it (100). Antibody titre, methodology employed, and the volume of convalescent plasma administered all vary widely across the studies that have investigated this approach in COVID-19. It should be further noted that in some trials, the antibody titre reported for eligibility was higher than the reported antibody titre in the donor plasma that was used because of the differences in methodology used for the two assessments (e.g. total IgG for donor eligibility with subsequent assessment of the specific neutralizing antibody titre (101)). There is clear uncertainty surrounding the dose of neutralizing antibodies given in different trials and this uncertainty is summarised as follows: For trials in severe/critical patients: • No cut-off in neutralizing antibody titre of the donor was applied in 9/16 studies. • Antibody titre of the donor plasma was not recorded in 12/16 trials, meaning the titre may have been high or may have been low. However, in 3 of the trials in which donor titre was not recorded, a lower cut-off was applied at a titre of either 1:160 (for 2 trials) or 1:400. • The largest trial (RECOVERY) did not report donor antibody titres although only donors with a titre above 1:100 were eligible • One (1/16) trial did not provide information on what volume of plasma was administered meaning volume could have been high or could have been low. • Both volume and donor titre were only known for 6/16 trials. Donor titres were 1:80, 1:87, 1:300, 1:320, 1:526, and 1:640 with volumes of 300, 500, 400–600, approx. 480, 750–975, and 300 mL, respectively (estimated dose range of 6-fold). For trials in non-severe patients: • Only three trials were conducted in non-severe patients using antibody titres of 1:40, 1:292, and 1:3200 with volumes administered of 250–300 mL, 400 mL and 250 mL, respectively (estimated dose range of 100-fold). • Two trials studied both non-severe and severe/critical patients, one of which didn’t record antibody titre, and the other which used 200–250 +/- 75 mL of plasma with a titre of 1:160. 6.10 Casirivimab-imdevimab (neutralizing monoclonal antibodies) (published 24 September 2021) Info Box Recommendations concerning neutralizing monoclonal antibodies (casirivimab-imdevimab) for patients with non-severe, severe or critical COVID-19 were published on 24 September 2021 as the sixth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the availability of pre-prints of four trials that were part of the larger adaptive randomized master protocol addressing patients with non-severe illness, and of the RECOVERY trial addressing severe and critically ill patients (9)(10)(11). Following the publication of a previous conditional recommendation for casirivimab-imdevimab, additional preclinical evidence has emerged (see Mechanism of action) (102). There is a substantial body of pre-clinical in vitro data, and a confirmatory in vivo evaluation, demonstrating lack of efficacy of casirivimab-imdevimab against the Omicron BA.1 variant (see Mechanism of action). As a result, casirivimab-imdevimab is no longer recommended for COVID-19 treatment except in cases where rapid viral genotyping is available and confirms infection with a SARS-CoV-2 variant (such as Delta) that is susceptible to the neutralizing activity of this combination of monoclonal antibodies. The GDG notes that several therapeutic alternatives are available for patients with non-severe COVID-19 at highest risk of hospitalization (see Section 6.1 and remarks below the recommendation). No changes were made to the convalescent plasma recommendations in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 76 of 142 For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Dosing and administration route: Intravenous total dose of the monoclonal antibody combination differed in the non-severe trials, ranging from total dose 1200 mg–8000 mg (600 mg–4000 mg each antibody), demonstrating efficacy at all doses, including the lowest tested, 1200 mg total dose (600 mg of each antibody). In the face of limited access and resource considerations, health systems will face choices concerning dose of casirivimab-imdevimab as well as intravenous or subcutaneous injections. Please see the acceptability and feasibility section (under Evidence to Decision) for some deliberations to help in making these choices within the possible range of 1200 mg–2400 mg total dose. Monitoring: Although the available trials have not convincingly shown that casirivimab-imdevimab results in allergic reactions, the possibility remains. To be administered through an intravenous line containing a sterile in-line or add-on 0.2 micron filter. Following administration, patients should undergo monitoring for severe anaphylaxis. Evidence To Decision Conditional recommendation for We suggest treatment with casirivimab-imdevimab where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e. excluding Omicron BA.1) (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk of being hospitalized. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies, including sotrovimab and casirivimab-imdevimab. • The GDG concluded that nirmatrelvir-ritonavir may represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. Updated In non-severe patients, casirivimab-imdevimab probably reduces the risk of hospitalization and duration of symptoms. Casirivimab-imdevimab is unlikely to have serious adverse effects, including allergic reactions. Benefits and harms Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represents the major source of indirectness for which the GDG rated down the certainty of the evidence (31). In addition, the GDG felt that there was some indirectness because of the possible emergence of variants in which effectiveness may be reduced. The GDG thus rated down the certainty of evidence to moderate for hospitalization and duration of symptoms. The GDG rated down evidence certainty to moderate for allergic reactions because of imprecision but considered the finding of no serious adverse effects to represent high certainty evidence. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients at typical low risk of hospitalization would decline casirivimab-imdevimab and only those at higher risk (e.g. unvaccinated, older, or immunosuppressed) would choose the treatment. Values and preferences Acceptability and feasibility Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 77 of 142 Justification A combination of the evidence, values and preferences, and feasibility contributed to the conditional recommendation for the use of casirivimab-imdevimab only in patients with non-severe COVID-19 at highest risk of hospitalization. Although there is moderate certainty evidence of a substantial relative risk reduction in hospitalization, only a minority of patients who are at highest risk are likely to achieve important benefit. In routine care of those with non-severe COVID-19, there is a lack of tools to reliably identify those at highest risk of hospitalization. This clinical complexity, combined with the limited availability of the drug and need for parenteral administration route for a group of patients who are typically cared for in the community, present a range of challenges for care that need to be addressed by health care systems. Applicability The applicability of this recommendation to children is currently uncertain, as the included RCTs enrolled adults. The GDG had no reason to think that children with COVID-19 would respond any differently to treatment with casirivimab-imdevimab. However, the risk of hospitalization in children is generally extremely low and the GDG inferred that in the absence of immunosuppression or another significant risk factor children should not receive the intervention. The GDG noted that casirivimab-imdevimab is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This further supports the guidance that casirivimab-imdevimab be reserved for those at highest risk of hospitalization. Major feasibility challenges include limited production of casirivimab-imdevimab and, for outpatients, the requirement for intravenous administration. Regarding intravenous administration, it is likely that specialized clinics with adequate amounts of the antibodies and personnel who will ensure safe and effective administration of the intervention will be required. For the intervention to achieve substantial use, health systems will have to address these challenges. Choosing a dose: Different doses of the monoclonal antibody combination were used in different trials, and health systems will face the choice of which dose to use and this can be informed by values and preferences. If one’s priority is to ensure giving as many people as possible the opportunity to benefit from treatment, one might use the lowest effective dose offered in the studies of non-severe patients, 1200 mg total dose (600 mg of each antibody) (103). If one’s priority is on ensuring effectiveness in every individual who receives treatment, and minimizing the risk of emergence of resistance, one might use a higher total intravenous dose of 2400 mg (1200 mg of each antibody). Administration route: A similar value and preference issue arises in choosing between intravenous administration – used in the four trials included in the LNMA (from a larger adaptive randomized master protocol) (104) – and subcutaneous administration, which has been used in the prophylactic trial (105). Intravenous administration will achieve maximum drug concentrations faster than subcutaneous administration; however, both will achieve exposure above the proposed therapeutic threshold. If one’s priority is to ensure maximum effectiveness in every individual who receives treatment, one might choose intravenous administration. If one’s priority is, in the face of practical difficulties of widespread intravenous administration in the community, to ensure giving as many people as possible the opportunity to benefit from treatment, one might ensure the availability of subcutaneous administration as an alternative. Volumes that can be administered subcutaneously are limited to the lowest dose, which is a total dose 1200 mg (600 mg of each antibody). Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary For patients with non-severe COVID-19, the LNMA (2) pooled data from four trials that enrolled 4722 patients randomized to casirivimab-imdevimab or usual care (104). All trials were registered and presented in pre-prints when the data were reviewed by the GDG. The Table shows trial characteristics. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 78 of 142 The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with non-severe COVID-19, with certainty ratings. Specific considerations regarding baseline risk estimates informing absolute estimates of effect For hospital admission, the key outcome driving the recommendation in favour of casirivimab-imdevimab, we used a baseline risk of 4.2% (42 in 1000) based on the median of the control arm of the four RCTs contributing to the evidence. These trials recruited patients at elevated risk of being hospitalized to increase statistical power in detecting potential treatment effects. The baseline risk is therefore appreciably higher than the risk for many patients with non-severe COVID-19. Subgroup analysis We found no evidence of subgroup effects on age or time from onset of illness in patients with non-severe COVID-19. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.57 (CI 95% 0.26 — 1.2) Based on data from 4722 participants in 4 studies. (Randomized controlled) 6 per 1000 Difference: 3 per 1000 3 fewer per 1000 ( CI 95% 4 fewer — 1 more ) Moderate Due to serious indirectness 1 Casirivimab-imdevimab do not have an important effect on mortality. Mechanical ventilation Odds ratio 0.22 (CI 95% 0.03 — 1.21) Based on data from 3432 participants in 2 studies. (Randomized controlled) 8 per 1000 Difference: 2 per 1000 6 fewer per 1000 ( CI 95% 8 fewer — 2 more ) Moderate Due to serious indirectness 2 Casirivimab-imdevimab probably do not have an important effect on mechanical ventilation. Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 35 per 1000 Difference: 10 per 1000 25 fewer per 1000 ( CI 95% 29 fewer — 18 fewer ) Moderate Due to serious indirectness 3 Casirivimab-imdevimab probably reduce admission to hospital. Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 60 per 1000 Difference: 18 per 1000 42 fewer per 1000 ( CI 95% 49 fewer — 30 fewer ) Moderate Due to serious indirectness 4 Casirivimab-imdevimab probably reduce admission to hospital. Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 100 per 1000 Difference: 31 per 1000 69 fewer per 1000 ( CI 95% 81 fewer Moderate Due to serious indirectness 5 Casirivimab-imdevimab probably reduce admission to hospital. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 79 of 142 — 49 fewer ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. There is substantial variability in baseline risk of death between patients. Casirivimab-imdevimab may confer an important benefit in patients at higher risk of death. 2. Indirectness: serious. There is substantial variability in baseline risk of mechanical ventilation between patients. Casirivimab-imdevimab may confer an important benefit in patients at higher risk of mechanical ventilation. 3. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 4. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 5. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 6. Imprecision: serious. 7. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 8. Imprecision: very serious. Adverse effects leading to drug discontinuation Based on data from 5284 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 CI 95% High Casirivimab-imdevimab do not result in an important increase in adverse effects leading to drug discontinuation. Allergic reactions Based on data from 15 406 participants in 4 studies. (Randomized controlled) 3 per 1000 Difference: 9 per 1000 6 more per 1000 ( CI 95% 1 fewer — 29 more ) Moderate Due to serious imprecision 6 Casirivimab-imdevimab probably do not result in an important increase in allergic reactions. Time to symptom resolution Lower better Based on data from 3084 participants in 2 studies. (Randomized controlled) 9 (Mean) Difference: 4.9 (Mean) MD 4.1 fewer ( CI 95% 5.7 fewer — 1.8 fewer ) Moderate Due to serious indirectness 7 Casirivimab-imdevimab probably reduce time to symptom improvement. Duration of hospitalization (not in hospital at baseline) Lower better Based on data from 111 participants in 2 studies. (Randomized controlled) 9.6 (Mean) Difference: 8.2 (Mean) MD 1.4 fewer ( CI 95% 4.6 fewer — 1.8 more ) Low Due to very serious imprecision 8 Casirivimab-imdevimab may not have an important impact on duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 80 of 142 For patients with severe or critical COVID-19 Practical Info Dosing and administration route: Intravenous dosing of the monoclonal antibody combination in the RECOVERY trial that enrolled severe and critical COVID-19 was a total dose of 8000 mg (4000 mg for each antibody), whereas the dose differed in the four trials in non-severe patients (from a larger adaptive randomized master protocol), ranging from intravenous total dose of 1200 mg–8000 mg. In the face of limited access and resource considerations, health systems will face a choice concerning the dose of casirivimab-imdevimab. Please see the acceptability and feasibility section (under Evidence to Decision) for deliberations to help in making these choices within the possible range of 2400 mg–8000 mg total dose. Diagnostic testing: Tests to identify patients with seronegative status at the time patients present with severe or critical COVID-19 warrant rapid serological tests with adequate performance characteristics. Health care systems would need to implement such tests, as outlined in the acceptability and feasibility section. Monitoring: Although the available trials have not convincingly shown that casirivimab-imdevimab results in allergic reactions, the possibility remains. Administer through an intravenous line containing a sterile in-line or add-on 0.2 micron filter. Following infusion, patients should undergo monitoring for allergic reactions. Evidence To Decision Conditional recommendation for We suggest treatment with casirivimab-imdevimab for patients with seronegative status, and where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e. excluding Omicron BA.1) (conditional recommendation for). • With benefits of casirivimab-imdevimab observed only in patients with seronegative status, clinicians will need to identify these patients by credible tests available at the point of care to appropriately apply this recommendation (see Evidence to Decision section). • Treatment with casirivimab-imdevimab is in addition to the current standard of care, which includes corticosteroids and IL-6 receptor blockers. Updated In the overall population of patients with severe and critical COVID-19, casirivimab-imdevimab may not have an impact on mortality and the impact on mechanical ventilation and duration of hospitalization is very uncertain. A credible subgroup effect demonstrated that casirivimab-imdevimab probably reduces mortality in patients who are seronegative, with the absolute effects ranging from 39 fewer per 1000 (95% CI 62 fewer-13 fewer) in the severely ill to 69 fewer (95% CI 110 fewer-23 fewer) in the critically ill. In seronegative patients, the intervention possibly reduces the need for mechanical ventilation (absolute effect estimate 42 fewer per 1000; 95% CI 74 fewer-6 fewer). Aside from the credible subgroup effect for serological status, we 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. Benefits and harms In patients with severe and critical COVID-19, evidence for mortality was of low certainty because of imprecision and high likelihood that casirivimab-imdevimab has, 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 given additional concerns with risk of bias. For patients with severe and critical COVID-19 who are seronegative, evidence for mortality was rated as moderate as a result of concerns regarding imprecision (the confidence interval includes effects as small as 14 in 1000 that some patients may perceive as trivial) and indirectness (variants may emerge in which casirivimab-imdevimab antibodies may have reduced effect). For mechanical ventilation, the GDG noted risk of bias from lack of blinding as an additional concern, resulting in low certainty evidence. For duration of hospitalization, the GDG also found very serious imprecision, resulting in very low certainty evidence. Certainty of the Evidence Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 81 of 142 Applying the agreed values and preferences (see Section 7), the GDG inferred that most if not all well-informed patients with severe or critical COVID-19 and seronegative status would choose to receive casirivimab-imdevimab. Other patients – those whose are seropositive or whose status is uncertain – are likely to decline the intervention. Although the GDG focused on an individual patient perspective, they also considered a population perspective in which feasibility, acceptability, equity and cost are important considerations. In this case, feasibility concerns played an important role in the conditional recommendation. For the severe and critical patients, both limited availability of therapeutics and the requirement for serological testing as part of clinical decision-making to identify the seronegative patients proved important. Values and preferences Cost and availability Given the cost and availability of casirivimab-imdevimab, and the challenges associated with serological testing, the obstacles to ensuring access in low- and middle-income countries may prove formidable. Thus, the panel’s suggestion that patients who are seronegative receive the intervention may exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, the recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Acceptability and feasibility Supply of casirivimab-imdevimab is likely to be limited, raising accessibility and possibly rationing challenges. In addition, benefit requires identification of serological status at the time patients present with severe or critical COVID-19. The availability of rapid and accurate serological tests as well as dosing and administration route for the drug are therefore key factors to consider for health care systems. Rapid serological tests: Tests with performance characteristics similar to the reference standard test used to characterize seronegative patients in the RECOVERY trial, i.e. the Oxford fluorescent-based ELISA assay for serum IgG against the SARS- CoV-2 spike protein, with an arbitrary cut-off determined by a panel of positive controls, are available and potentially affordable. Some lateral flow assays may be suitable and can usually be performed in several minutes (106)(107)(108). Health care systems must, however, gain expertise in choosing and implementing a rapid test or test, choosing those most applicable to their setting.. Choosing a dose: The clinical trial in severe and critical patients (RECOVERY) tested a total dose of 8000 mg (4000 mg of each antibody) casirivimab-imdevimab; clinical trials in non-severe patients have used total doses of 1200 mg–8000 mg (600 mg–4000 mg of each) with similar effects on decreasing the need for hospitalization. Pharmacokinetic profiles of casirivimab-imdevimab in non-severe with COVID-19 are available at total doses of 1200 mg–8000 mg (600 mg–4000 mg of each monoclonal antibody) (104). This study demonstrated that the target therapeutic concentrations were achieved rapidly in serum and maintained for 28 days even at the lowest total dose of 1200 mg (600 mg of each antibody), although serum concentrations of the drug were noted to vary considerably between individuals. Therefore, using doses lower than used in the RECOVERY trial (8000 mg total dose) for treatment of severely and critically ill patients may achieve the same benefit. On the other hand, it is theoretically plausible but untested that pharmacokinetic differences in severe and critical patients, when compared with non-severe, may reduce drug exposure (see Mechanism of action). This would increase the risk of sub-optimal drug exposure in some individuals, which in turn could increase the risk of therapeutic failure and the emergence of viral resistance. In the absence of clinical data on treatment of severe and critical patients with doses lower than 8000 mg, making a choice on which dose to use can be informed by values and preferences. If one’s priority is ensuring effectiveness in every individual who receives treatment, and minimizing the risk of emergence of resistance, one might use the total intravenous dose of 8000 mg (4000 mg of each antibody). If one’s priority is, in the face of limited drug availability and high cost, giving as many people as possible an opportunity to benefit from treatment, one might use an intravenous dose as low as a total of 2400 mg (1200 mg of each antibody). At a time of drug shortage, it may be necessary to prioritize use of casirivimab-imdevimab through clinical triage. One possibility is to prioritize patients with the highest baseline risk for mortality (e.g. those with critical disease over those with Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 82 of 142 Justification In patients with severe or critical illness, the conditional recommendation in favour of casirivimab-imdevimab use reflects the likelihood that any benefits are restricted to patients who are seronegative. In the RECOVERY trial, which provided all the evidence in severe and critical patients, serological status at baseline was assessed in a pre-planned but retrospective analysis using a laboratory-based anti-spike protein assay. In order to translate the trial findings into clinical practice, assessment of serological status will need to become integrated into a clinical decision pathway before treatment is administered. 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 and relatively inexpensive tests with adequate performance characteristics are available and should see increasing use in settings in which casirivimab-imdevimab is available for administration to these patients. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. Fortunately, very few children become critically ill with COVID-19. For those who do and are seronegative, it is possible they may benefit from casirivimab-imdevimab. Lack of data precluded the GDG from making specific recommendations for other special populations, such as pregnant women. severe disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite consistent relative effects (OR 0.85 for mortality) with casirivimab-imdevimab in seronegative patients, the absolute risk reduction for mortality in the critically ill would be 69 fewer deaths per 1000 (95% CI 110 to 23 fewer deaths) and in the severely ill would be 39 fewer deaths per 1000 (95% CI 62 to 13 fewer deaths). Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course and avoiding casirivimab-imdevimab therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller). Clinical Question/ PICO Population: Patients with severe or critical COVID-19, seronegative Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary The LNMA was informed by one large trial (RECOVERY) in patients with severe and critical illness that enrolled 9785 patients, most of whom received corticosteroids (109). The trial was registered and presented in pre-prints when the data was reviewed by the GDG. The Table shows trial characteristics. The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with severe and critical COVID-19 and seronegative status, with certainty ratings. Specific considerations regarding baseline risk estimates informing absolute estimates of effect In severe and critical COVID-19 patients, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. To inform baseline risk estimates for mortality in seronegative patients, we identified the control arm of the RECOVERY trial as the best source. For patients with seronegative status, risk of death in both severe (26%; 260 per 1000) and critical (46%; 460 per 1000) illness is substantially higher than for the overall population. Thus, seronegative patients represent a very high risk population, leading to substantial absolute risk reductions in mortality (3.9% in the severe and 6.9% in the critical) despite the modest 15% relative risk reduction. Subgroup analysis A highly credible subgroup effect demonstrated that casirivimab-imdevimab likely reduces mortality in patients who are Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 83 of 142 seronegative but not in those who are seropositive. The credibility of the subgroup effect was evaluated using the ICEMAN tool (110). The credibility of the subgroup effect was strongly supported by: an a priori hypothesis with a specified direction; a small number of such hypotheses; evidence based on a within-study comparison; a suggestion of a similar subgroup effect in mechanical ventilation; and an interaction p-value of 0.001. Fig. 2 presents the forest plot depicting the point estimate and confidence interval around the effects on mortality in patients with seropositive and seronegative status, demonstrating benefit in those with seronegative status, suggesting harm in those with seropositive status, and no overlap in the confidence intervals, a result corresponding to the p=0.001 in the test of interaction (109). Fig. 2. Mortality, in seropositive and seronegative patients with severe and critical COVID-19 CI: confidence interval, RR: relative risk. Very low certainty evidence raises the possibility of shorter hospitalization in seronegative patients. Aside from the reported subgroup effects on serological status, we found no evidence of subgroup effects on age, time from onset of illness, and severity (comparing severe and critically ill patients). Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Severe disease Relative risk 0.85 (CI 95% 0.76 — 0.95) Based on data from 2823 participants in 1 study. (Randomized controlled) 260 per 1000 Difference: 221 per 1000 39 fewer per 1000 ( CI 95% 62 fewer — 13 fewer ) Moderate Due to concerns with imprecision and indirectness 1 Casirivimab-imdevimab probably reduce mortality. Mortality Critical disease Relative risk 0.85 (CI 95% 0.76 — 0.95) Based on data from 2823 participants in 1 study. (Randomized controlled) 460 per 1000 Difference: 391 per 1000 69 fewer per 1000 ( CI 95% 110 fewer — 23 fewer ) Moderate Due to concerns with imprecision and indirectness 2 Casirivimab-imdevimab probably reduce mortality. Mechanical ventilation Relative risk 0.87 (CI 95% 0.77 — 0.98) Based on data from 2410 participants in 1 study. (Randomized controlled) 320 per 1000 Difference: 278 per 1000 42 fewer per 1000 ( CI 95% 74 fewer — 6 fewer ) Low Due to concerns with risk of bias, imprecision, and indirectness 3 Casirivimab-imdevimab may reduce mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 84 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. Single study. 2. Imprecision: serious. Single study. 3. Risk of bias: serious. Imprecision: serious. 4. Risk of bias: serious. Indirectness: serious. Imprecision: very serious. Duration of hospitalization Based on data from 3153 participants in 1 study. (Randomized controlled) The median duration of hospital stay was 4 days shorter with casirivimab- imdevimab (13 days vs. 17 days). Very low Due to serious risk of bias, serious indirectness, and very serious imprecision 4 The impact on duration of hospitalization is very uncertain. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary The NMA evidence summary was informed by one large trial (RECOVERY) in patients with severe and critical illness that enrolled 9785 patients, most of whom received corticosteroids (109). The trial was registered and presented in preprints when the data was reviewed by the GDG. The Table shows trial characteristics. The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Critical or severe disease Odds ratio 0.94 (CI 95% 0.86 — 1.03) Based on data from 9785 participants in 1 study. (Randomized controlled) 130 per 1000 Difference: 122 per 1000 8 fewer per 1000 ( CI 95% 18 fewer — 4 more ) Low Due to serious indirectness and imprecision 1 Casirivima-imdevimab may not have an important effect on mortality. Mechanical ventilation Odds ratio 0.95 (CI 95% 0.87 — 1.04) Based on data from 6637 participants in 1 study. (Randomized controlled) 86 per 1000 Difference: 82 per 1000 4 fewer per 1000 ( CI 95% 11 fewer — 3 more ) Very low Due to serious risk of bias, indirectness, and imprecision 2 The impact on mechanical ventilation is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 85 of 142 6.10.1 Mechanism of action Casirivimab and imdevimab are two fully human antibodies (REGN10933 and REGN10987). Their mechanism of action is very plausible: they bind to the SARS-CoV-2 spike protein (111) and have demonstrated antiviral activity in rhesus macaques and Syrian golden hamsters (112). Pharmacokinetic data in patients with non-severe COVID-19 show that antiviral concentrations of both antibodies are achieved and maintained for at least 28 days after intravenous administration of the combination at a total dose of 1200 mg (600 mg each antibody) or above (42). Antiviral concentrations are also achieved and maintained using a subcutaneous total dose of 1200 mg (600 mg of each antibody) in uninfected individuals for prophylaxis (105). Half-lives range from 25 to 37 days for both antibodies. Data are currently unavailable for the pharmacokinetics of casirivimab and imdevimab in severe and critical COVID-19, which are important because serum concentrations of other monoclonal antibodies have been reported to be lower during systemic inflammation and correlated with albumin and CRP levels (113). Data available also suggest that when delivered in combination, activity remains for currently circulating variants of concern (114). While the mechanism is plausible, it was postulated that administration might have differential effects in patients who have produced their own anti-SARS-CoV-2 spike protein antibodies (hereafter seropositive) compared with those who have not (hereafter seronegative). It was hypothesized that effects might be larger, or restricted to, seronegative individuals who have not yet mounted an effective antibody response. Data describing the in vitro neutralization of different variants by monocolonal antibodies are collated on the NIH NCATS OpenData Portal (https://opendata.ncats.nih.gov/variant/activity). Several reports have demonstrated that in vitro neutralization of pseudovirus containing the BA.1 Omicron spike protein and in vitro neutralization of authentic BA.1 Omicron virus is dramatically reduced or lost for casirivumab and imdevimab when studied individually, and completely lost when both monoclonal antibodies are combined. Furthermore, the combination of casirivumab and imdevimab has no impact upon subgenomic viral RNA in the lungs or nasal turbinate of K18 human ACE2 transgenic mice infected with BA.1 Omicron Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Imprecision: serious. 2. Risk of bias: serious. Indirectness: serious. Imprecision: serious. 3. Imprecision: serious. 4. Risk of bias: serious. Imprecision: very serious. Allergic reactions Based on data from 15 406 participants in 4 studies. (Randomized controlled) 3 per 1000 Difference: 9 per 1000 6 more per 1000 ( CI 95% 1 fewer — 29 more ) Moderate Due to serious imprecision 3 Casirivimab-imdevimab probably do not result in an important increase in allergic reactions. Adverse effects leading to drug discontinuation Based on data from 5284 participants in 4 studies. (Randomized controlled) 2 per 1000 Difference: 1 per 1000 1 fewer per 1000 ( CI 95% 0 more — 1 more ) High Casirivimab-imdevimab do not result in an important increase in adverse effects leading to drug discontinuation. Duration of hospitalization Based on data from 9785 participants in 1 study. (Randomized controlled) Patients in both groups had the same median duration of hospitalization (10 days). Very low Due to serious risk of bias and very serious imprecision 4 The impact on duration of hospitalization is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 86 of 142 do not support activity of the casirivumab and imdevimab combination against the BA.1 Omicron variant. 6.11 Interleukin-6 receptor blockers (published 6 July 2021) For patients with severe or critical COVID-19 Practical Info Route: IL-6 receptor blockers are administered intravenously for the treatment of patients with severe or critical COVID-19; subcutaneous administration is not used in this case. IL-6 receptor blocker therapy should be administered in combination with systemic corticosteroids, which may be administered both orally and intravenously, with due consideration to their high bioavailability but possible malabsorption in the case of intestinal dysfunction with critical illness. Duration: Tocilizumab and sarilumab are administered as single intravenous doses, typically over 1 hour. A second dose may be administered 12 to 48 hours after the first dose; this was offered variably in major clinical trials at the discretion of treating clinicians if a clinical response was felt to be inadequate. Duration of concurrent systemic corticosteroids is typically up to 10 days, though may vary between 5 and 14 days. Dose: Tocilizumab is dosed at 8 mg per kilogram of actual body weight, up to a maximum of 800 mg. Sarilumab is most commonly dosed at 400 mg, consistent with what was used in REMAP-CAP. Renal dose adjustment is not currently warranted for either drug. Monitoring: Routine bloodwork including neutrophil count, platelets, transaminases, and total bilirubin should be checked prior to initiation of therapy. All patients should be monitored for signs and symptoms of infection, given the increased risk with immunosuppression in addition to systemic corticosteroids. Patients on longer term IL-6 receptor blocker therapy are at risk of active tuberculosis, invasive fungal infections and opportunistic pathogens. Risks and benefits of therapy should be considered carefully in patients with any active, severe infection other than COVID-19; caution is advised when considering the use of tocilizumab in patients with a history of recurring or chronic infections or with underlying conditions which may predispose them to infections. Timing: IL-6 receptor blockers should be initiated with systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. That being said, IL-6 receptor blockers have been administered early in the course of Info Box The recommendation concerning IL-6 receptor blockers (tocilizumab or sarilumab) was published on 6 July 2021 as the fifth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the publication of RECOVERY and REMAP-CAP trial publications in February 2021, and new trial data from 1020 patients randomized head-to-head to either tocilizumab or sarilumab in REMAP-CAP being made available to the WHO on 1 June 2021. No changes were made to the IL-6 receptor blocker recommendation in this eleventh version of the guideline. WHO has made a strong recommendation for JAK inhibitors, specifically baricitinib, in patients with severe and critical COVID-19. An IL-6 receptor blocker and baricitinib should not be given together and should be viewed as alternatives. These new considerations are provided under ‘Justification’ for the recommendation for IL-6 receptor blockers, and are unchanged in this eleventh version of the guideline. Strong recommendation for We recommend treatment with IL-6 receptor blockers (tocilizumab or sarilumab) (strong recommendation for). • Corticosteroids have previously been strongly recommended in patients with severe and critical COVID-19 (see Section 6.15), and we recommend patients meeting these severity criteria should now receive both corticosteroids and IL-6 receptor blockers. • Baricitinib, a JAK inhibitor, is now recommended for the treatment of patients with severe and critical COVID-19 (see Section 6.7). An IL-6 receptor blocker and baricitinib should not be given together and should be viewed as alternatives. The choice of whether to use baricitinib or an IL-6 receptor blocker depends on availability as well as clinical and contextual factors (see Justification). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 87 of 142 (https://www.biorxiv.org/content/10.1101/2022.01.23.477397v1.full.pdf+html). Therefore, currently available preclinical data hospitalization in the included trials and clinicians may consider this approach if possible. See section on resource implications, equity and human rights. Evidence To Decision IL-6 receptor blockers reduce mortality and need for mechanical ventilation based on high certainty evidence. Low certainty evidence suggests they may also reduce duration of mechanical ventilation and hospitalization (3)(115)(116). The evidence regarding the risk of serious adverse events (SAEs) is uncertain. Low certainty evidence suggested that the risk of bacterial infections in the context of immunosuppression treatment with IL-6 receptor blockers may be similar to usual care (1). However the GDG had some concerns that, given the short-term follow-up of most trials and the challenges associated with accurately capturing adverse events such as bacterial or fungal infection, the evidence summary may under- represent the risks of treatment with IL-6 receptor blockers. Furthermore, the trials of IL-6 receptor blockers that inform this recommendation were mostly performed in high-income countries where the risk of certain infectious complications may be less than in some other parts of the world, and so the generalizability of the data on adverse events is unclear. We did not have any data examining differential risk of harm based on whether patients received one or two doses of IL-6 receptor blocker. Subgroup analyses indicated no effect modification based on IL-6 receptor blocker drug (sarilumab or tocilizumab) or disease severity (critical vs severe) and therefore this recommendation applies to all adult patients with either severe or critical COVID-19 (110). We were unable to examine subgroups based on elevation of inflammatory markers or age due to insufficient trial data (see Research evidence). Subgroup analyses evaluating baseline steroid use found greater benefit of IL-6 receptor blockers in patients receiving steroids compared with those who were not (p=0.026), demonstrating that steroid use does not abolish and might enhance the beneficial effect of IL-6 receptor blockers. Since steroids are already strongly recommended in patients with severe and critical COVID-19, we did not formally evaluate the credibility of this subgroup analysis as there would be no rationale for a subgroup recommendation for patients not receiving corticosteroids. Benefits and harms Certainty of evidence was rated as high for mortality and need for mechanical ventilation. Certainty in duration of mechanical ventilation was rated as low due to serious risk of bias due to concerns regarding lack of blinding in included trials, and for imprecision as the lower limit of the confidence interval suggested no effect. Certainty in duration of hospitalization was rated as low due to serious risk of bias from lack of blinding in included trials, and for inconsistency related to differences in point estimates and lack of overlap in confidence intervals. Certainty in serious adverse events was rated as very low due to risk of bias related to lack of blinding and ascertainment bias, and very serious imprecision due to very wide confidence intervals which did not rule out important benefit or harm; certainty in risk of bacterial or fungal infections was rated as low due to similar concerns regarding serious risk of bias and serious imprecision. Certainty in evidence was rated as moderate when comparing the effect on mortality between tocilizumab and sarilumab due to issues with imprecision. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the majority of the GDG inferred that almost all well-informed patients would want to receive IL-6 receptor blockers. The benefit of IL-6 receptor blockers on mortality was deemed of critical importance to patients, despite the very low certainty around serious adverse events. The GDG anticipated little variation in values and preferences between patients for this intervention. Values and preferences Resource implications, equity and human rights Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 88 of 142 Justification When moving from evidence to the strong recommendation to use IL-6 receptor blockers (tocilizumab or sarilumab) in patients with severe or critical COVID-19, the GDG emphasized the high certainty evidence of improved survival and reduction in need for mechanical ventilation. Additional trial data from REMAP-CAP (see Research Evidence section) provided more conclusive evidence regarding the equivalence of tocilizumab and sarilumab. The GDG acknowledged the uncertain data regarding SAEs and bacterial infections, but felt that the evidence of benefit for the two most important patient outcomes warranted a strong recommendation. Costs and access were important considerations and it was recognized that this recommendation could exacerbate health inequities. Hopefully this strong recommendation will provide impetus to address these concerns and ensure access across regions and countries. The GDG did not anticipate important variability in patient values and preferences, and judged that other contextual factors would not alter the recommendation (see Evidence to Decision). Subgroup analyses The GDG did not find any evidence of a subgroup effect across patients with different levels of disease severity (severe vs critical), or by IL-6 receptor blocker drug (tocilizumab vs sarilumab). There were insufficient data to assess subgroup effect by elevation of inflammatory markers or age. Although the GDG considered a subgroup analysis of patients receiving corticosteroids at baseline as compared with those that were not, the panel did not see a need to consider subgroup recommendations for IL-6 receptor blockers in those not receiving corticosteroids as all severe and critical COVID-19 patients should be receiving corticosteroids (see previous strong recommendation below). Taken together, the GDG felt that the recommendation applies to both tocilizumab and sarilumab and all adult patients with severe or critical COVID-19. The role of IL-6 receptor blockers and baricitinib WHO has recently made a strong recommendation for baricitinib in patients with severe and critical COVID-19. Both classes of drugs are immune modulators with overlapping effects on immune responses. There is therefore a reasonable possibility that their effects on COVID-19 will not be additive. Moreover, it is possible that when given together, adverse effects, including secondary bacterial or fungal infection, will be greater. In the absence of evidence of incremental benefit of the drugs when given together, the GDG advises that clinicians do not administer the drugs together. See Justification section for JAK inhibitors and related Summary of Findings table (see Research evidence) for more detailed discussion regarding selecting between therapies. The GDG noted that, compared with some other candidate treatments for COVID-19, IL-6 receptor blockers are more expensive and the recommendation does not take account of cost-effectiveness. Currently, access to these drugs is challenging in many parts of the world, and without concerted effort is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation for IL-6 receptor blockers could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. At a time of drug shortage, it may be necessary to prioritize use of IL-6 receptor blockade through clinical triage (6). Many jurisdictions have suggested mechanisms for triaging use of these treatments. These include prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite consistent relative effects (OR 0.86 for mortality) with IL-6 receptor blockers, the absolute risk reduction for mortality in the critically ill would be 31 fewer deaths per 1000 (95% CI 11 to 47 fewer deaths) and in the severely ill would be 13 fewer deaths per 1000 (95% CI 5 to 19 fewer deaths). Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course and avoiding IL-6 receptor blocker therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller). Acceptability and feasibility As IL-6 receptor blockers require intravenous administration, this treatment would be primarily indicated for patients with severe and critical COVID-19 who require hospitalization. IL-6 receptor blockers are relatively easy to administer, and only require one, or at most, two doses. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 89 of 142 Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the GDG had no reason to think that children with COVID-19 would respond any differently to treatment with IL-6 receptor blockers. This is especially true given tocilizumab is used in children safely for other indications including polyarticular juvenile rheumatoid arthritis, systemic onset of juvenile chronic arthritis, and chimeric antigen receptor T-cell induced cytokine release syndrome. Sarilumab is not approved in children, so if an IL-6 receptor blocker is used in this population, tocilizumab is preferred. The GDG also recognized that in many settings children are commonly admitted to hospital with acute respiratory illnesses caused by other pathogens; as a result, it may be challenging to determine who is ill with severe COVID-19, even with a positive test, and therefore likely to benefit from IL-6 receptor blockade. There were similar considerations in regard to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. The drug may, however, cross the placental membrane, although it is uncertain what effect transient immunosuppression in the fetus may have and this should be weighed against the potential benefit for the mother. Clinical Question/ PICO Population: Patients with severe and critical COVID-19 Intervention: Baricitinib Comparator: Interleukin-6 receptor blockers Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.77 (CI 95% 0.53 — 1.1) Based on data from 2659 participants in 3 studies. (Randomized controlled) 118 per 1000 Difference: 96 per 1000 22 fewer per 1000 ( CI 95% 52 fewer — 9 more ) Low Due to serious imprecision and ongoing recruitment in a large RCT 1 Baricitinib may reduce mortality. Mechanical ventilation Odds ratio 1.01 (CI 95% 0.61 — 1.6) Based on data from 2434 participants in 2 studies. (Randomized controlled) 94 per 1000 Difference: 96 per 1000 2 more per 1000 ( CI 95% 38 fewer — 44 more ) Low Due to very serious imprecision 2 There may be little or no difference on mechanical ventilation. Adverse effects leading to drug discontinuation Based on data from 2309 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 1 per 1000 1 more per 1000 ( CI 95% 11 fewer — 15 more ) Moderate Due to serious imprecision 3 There is probably little to no difference in adverse effects leading to discontinuation. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 8.1 days (Median) Difference: 11.2 days (Mean) MD 3.1 more ( CI 95% 3.8 fewer — 9.9 more ) Very low Due to serious risk of bias, serious inconsistency, and very serious imprecision 4 The impact on hospital length of stay is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 90 of 142 Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. The credible interval includes no important difference. 2. Risk of bias: no serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: very serious. The credible interval includes important benefit and important harm. 3. Imprecision: serious. The credible interval includes small but important harm. 4. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Inconsistency: serious. The trials that studied interleukin-6 receptor blockers had discrepant results: some increased length of stay, others reduced length of stay. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. The credible interval includes no important difference. 6. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 13.8 days (Median) Difference: 11.6 days (Mean) MD 2.2 fewer ( CI 95% 5.3 fewer — 0.7 fewer ) Low Due to serious risk of bias and imprecision 5 Baricitinib may reduce duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 8.4 days (Median) Difference: 8.9 days (Mean) MD 0.5 more ( CI 95% 2.3 fewer — 3.2 more ) Low Due to serious risk of bias and imprecision 6 There may not be an important impact on time to clinical stability. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Interleukin-6 receptor blockers Comparator: Standard care Summary Evidence summary The LNMA (8) on IL-6 receptor blockers was informed by 30 RCTs with 10 618 participants and provided relative estimates of effect for all patient-important outcomes except mortality, which came from the prospective meta-analysis (PMA) (116). Of the trials included in the LNMA, all were registered and examined patients with severe or critical illness related to COVID-19 (trial characteristics table available upon request). Of the trials, 37% were published in peer- reviewed journals, 3% were available as preprints and 60% were completed but unpublished. The evidence summary for mortality was based on 27 RCTs and 10 930 participants from the PMA (116). We used the PMA for mortality as it included some additional unpublished data that reported on this outcome. The GDG recognized that usual care is likely variable between centres and regions, and has evolved over time. However, given all of the data come from RCTs, use of these co-interventions that comprise usual care would be expected to be balanced between study patients randomized to either the intervention or usual care arms. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 91 of 142 The GRADE Summary of Findings table shows the relative and absolute effects of IL-6 receptor blockers compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis All included RCTs evaluated IL-6 receptor blockers exclusively in severely or critically ill adults with COVID-19 requiring hospitalization. The GDG requested subgroup analyses based on age (< 70 years versus older), disease severity (severe versus critical), levels of inflammatory markers and baseline corticosteroid use for the following outcomes: mortality, need for and duration of mechanical ventilation, duration of hospitalization, and risks of SAEs and bacterial infections. Based on subgroup analyses, the GDG determined that there was no subgroup effect across any pre-specified outcomes of interest based on disease severity. The GDG considered the results of a subgroup analysis of all included RCTs based on systemic corticosteroid use for the outcome of mortality. The analysis suggested that the relative effects of IL-6 receptor blockers varied as a function of the use of systemic corticosteroids at baseline. Crucially, steroids did not abolish and may even enhance the beneficial effect of IL-6 receptor blockers on mortality. For reasons described below, the GDG did not formally evaluate the credibility of this subgroup analysis. When comparing tocilizumab and sarilumab, based on the PMA, there was no evidence of a subgroup effect (116). However, there were more data, and therefore greater precision, for tocilizumab+steroids versus steroids alone (OR 0.77, 95% CI 0.68–0.87) as compared with sarilumab+steroids versus steroids alone (OR 0.92, 95% CI 0.61–1.38). In addition to these subgroup data, the GDG reviewed head-to-head data from REMAP-CAP investigators which demonstrated no difference between tocilizumab as compared with sarilumab in a population of patients all receiving corticosteroids (36.5% mortality with tocilizumab, 33.9% mortality with sarilumab). The NMA estimate of tocilizumab+steroids versus sarilumab+steroids, incorporating both direct and indirect data, provided moderate certainty data of no difference between the drugs (OR 1.07, 95% CI 0.86–1.34) (1)(3). Outcome Timeframe Study results and measurements Comparator Standard care Intervention IL-6 receptor blockers Certainty of the Evidence (Quality of evidence) Plain language summary Mortality (severe and critically ill patients) Odds ratio 0.86 (CI 95% 0.79 — 0.95) Based on data from 10 930 participants in 27 studies. 1 (Randomized controlled) 130 per 1000 Difference: 114 per 1000 16 fewer per 1000 ( CI 95% 24 fewer — 6 fewer ) High IL-6 receptor blockers reduce mortality. Mechanical ventilation Odds ratio 0.72 (CI 95% 0.57 — 0.9) Based on data from 5686 participants in 9 studies. 2 (Randomized controlled) 86 per 1000 Difference: 63 per 1000 23 fewer per 1000 ( CI 95% 35 fewer — 8 fewer ) High IL-6 receptor blockers reduce need for mechanical ventilation. Adverse events leading to drug discontinuation Odds ratio 0.5 (CI 95% 0.03 — 9.08) Based on data from 815 participants in 2 studies. 3 (Randomized controlled) 9 per 1000 Difference: 5 per 1000 4 fewer per 1000 ( CI 95% 0 more — 67 more ) Very low Due to serious risk of bias and very serious imprecision 4 The effect of IL-6 receptor blockers on adverse events leading to discontinuation is uncertain. Bacterial infections Odds ratio 0.95 (CI 95% 0.72 — 1.29) Based on data from 101 per 1000 96 per 1000 Low Due to serious risk of bias and IL-6 receptor blockers may not increase secondary bacterial Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 92 of 142 6.11.1 Mechanism of action IL-6 is a pleiotropic cytokine which activates and regulates the immune response to infections. Elevated IL-6 concentrations are associated with severe outcomes in COVID-19, including respiratory failure and death, although the role of IL-6 in disease pathogenesis is unclear. Tocilizumab and sarilumab are monoclonal antibodies approved for use in rheumatoid arthritis. They antagonize the membrane bound and soluble forms of the IL-6 receptor (IL-6R/sIL-6R). Tocilizumab is approved for intravenous use in rheumatoid arthritis Outcome Timeframe Study results and measurements Comparator Standard care Intervention IL-6 receptor blockers Certainty of the Evidence (Quality of evidence) Plain language summary 1. . Baseline/comparator: Primary study[15]. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19, adjusted for corticosteroids as part of standard of care (16% baseline risk x RR 0.79 for corticosteroids = 13%). The control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, was identified by the GDG panel as generally representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19. 2. Systematic review [3] . Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19, adjusted for corticosteroids as part of standard of care (16% baseline risk x RR 0.79 for corticosteroids = 13%). The control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, was identified by the GDG panel as generally representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19. 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. We used the median event rate for all patients randomized to usual care across included studies. Supporting references: [3], 4. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding and ascertainment bias. Imprecision: very serious. We downgraded due to very wide confidence intervals crossing the null. 5. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding and ascertainment bias. Imprecision: serious. Downgraded due to wide confidence intervals crossing the null. 6. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding. Imprecision: serious. We downgraded as the lower limit of the confidence interval was close to the null. 7. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding. Inconsistency: serious. Downgraded due to differences in point estimates and lack of overlap in confidence intervals. 3548 participants in 18 studies. (Randomized controlled) Difference: 5 fewer per 1000 ( CI 95% 26 fewer — 26 more ) serious imprecision 5 infections. Duration of mechanical ventilation Lower better Based on data from 1189 participants in 10 studies. (Randomized controlled) 14.7 (Mean) Difference: 13.5 (Mean) MD 1.2 lower ( CI 95% 2.3 lower — 0.1 lower ) Low Due to serious risk of bias and serious imprecision 6 IL-6 receptor blockers may reduce duration of mechanical ventilation. Duration of hospitalization Lower better Based on data from 6665 participants in 9 studies. (Randomized controlled) 12.8 (Mean) Difference: 8.3 (Mean) MD 4.5 lower ( CI 95% 6.7 lower — 2.3 lower ) Low Due to serious risk of bias and serious inconsistency 7 IL-6 receptor blockers may reduce duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 93 of 142 and sarilumab for subcutaneous use, although in COVID-19 both have been studied intravenously. At the studied doses in COVID-19, both medicines are expected to achieve very high levels of receptor occupancy based upon studies in rheumatoid arthritis (29). IL-6 receptor blockers are being repurposed in terms of indication but not in terms of the primary pharmacological mechanism of action. Efficacy in COVID-19 depends upon the importance of IL-6 signalling in the pathophysiology of the disease, rather than upon whether the doses used achieve target concentrations. 6.12 Ivermectin (published 31 March 2021) For patients with COVID-19, regardless of disease severity Practical Info The GDG made a recommendation against using ivermectin for treatment of patients with COVID-19 outside the setting of a clinical trial and therefore practical considerations are less relevant for this drug. Evidence To Decision Info Box The recommendation concerning ivermectin was published on 31 March 2021 as the fourth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the increased international attention on ivermectin as a potential therapeutic option. No changes were made to the ivermectin recommendation in this eleventh version of the guideline. We are aware of a few new, relatively small trials published since our recommendation was made and that one key trial has since been retracted given concerns about research fraud (117)(118). However, the updated evidence summary from the LNMA is consistent with our previously made recommendation. This updated evidence summary will be fully considered by the GDG in subsequent iterations of the guideline. Only in research settings We recommend not to use ivermectin, except in the context of a clinical trial (recommended only in research settings). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. A recommendation to only use a drug in the setting of clinical trials is appropriate when there is very low certainty evidence and future research has a large potential for reducing uncertainty about the effects of the intervention and for doing so at reasonable cost. The effects of ivermectin on mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral clearance remain uncertain because of very low certainty of evidence addressing each of these outcomes. Ivermectin may have little or no effect on time to clinical improvement (low certainty evidence). Ivermectin may increase the risk of SAEs leading to drug discontinuation (low certainty evidence). Subgroup analyses indicated no effect modification based on dose. We were unable to examine subgroups based on patient age or severity of illness due to insufficient trial data (see Research evidence). Therefore, we assumed similar effects in all subgroups. This recommendation applies to patients with any disease severity and any duration of symptoms. Benefits and harms For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral Certainty of the Evidence Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 94 of 142 Justification When moving from evidence to a recommendation on the use of ivermectin in patients with COVID-19 only in the context of a clinical trial, the GDG emphasized the high degree of uncertainty in the most critical outcomes such as mortality and need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased adverse events. The GDG did not anticipate important variability in patient values and preferences. Other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity did not alter the recommendation. Compared with previous drugs evaluated as part of the WHO Therapeutics and COVID-19: living guideline, currently there are far fewer RCT data available for ivermectin. The existing data on ivermectin also have a substantially higher degree of uncertainty, with included trials having enrolled substantially fewer patients with far fewer events. High degree of uncertainty The certainty in effect estimates for ivermectin on the main outcomes of interest, including mortality, is very low and therefore the effect of ivermectin on these outcomes remains uncertain. There are two domains that contribute to this uncertainty: serious risk of bias; and serious imprecision. Although 16 RCTs contributed to the evidence summary informing this drug, only five directly compared ivermectin with standard of care and reported mortality (119)(120)(121)(122)(123)(124)(125). Of note, and in keeping with our methodology, the LNMA team excluded quasi-randomized trials, or any RCT that did not use explicit randomization techniques. Of these five RCTs, two (119)(120) were at high risk of bias, due to inadequate blinding. One of these two trials (119) also started enrolling and randomizing patients prior to the protocol being publicly posted, another factor that contributes to an increased risk of bias. The potential impact of risk of bias is exemplified by subgroup analyses for mortality based on trial risk of bias. As demonstrated in the forest plot (Fig. 3), the pooled estimate across all five RCTs that directly compare ivermectin with standard care suggests a reduction in mortality with ivermectin, but this effect is not apparent if we only consider the trials at low risk of bias (which together contribute nearly two-thirds of the evidence). This finding increases the degree of uncertainty regarding the true effect of ivermectin on mortality. Consistent with the direct evidence, a similar phenomenon is observed with the indirect evidence comparing ivermectin to standard of care (via comparisons against clearance, the GDG considered the evidence of very low certainty. Evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also serious concerns related to risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias). For more details, see the Justification section for this recommendation. For other outcomes, including SAEs and time to clinical improvement, the certainty of the evidence was low. Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would want to receive ivermectin only in the context of a randomized trial, given that the evidence left a very high degree of uncertainty in effect on mortality, need for mechanical ventilation, need for hospitalization and other critical outcomes of interest and there was a possibility of harms, such as treatment-associated SAEs. The panel anticipated little variation in values and preferences between patients when it came to this intervention. Values and preferences Ivermectin is a relatively inexpensive drug and is widely available, including in low-income settings. The low cost and wide availability do not, in the GDG's view, mandate the use of a drug in which any benefit remains very uncertain and ongoing concerns regarding harms remain. Although the cost may be low per patient, the GDG raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe COVID-19 and other supportive care interventions. Also, use of ivermectin for COVID-19 would divert drug supply away from pathologies for which it is clearly indicated, potentially contributing to drug shortages, especially for helminth control and elimination programmes. Other endemic infections that may worsen with corticosteroids should be considered. If steroids are used in the treatment of COVID-19, empiric treatment with ivermectin may still be considered in Strongyloidiasis endemic areas, at the discretion of clinicians overseeing treatment, albeit not for treatment of COVID-19 itself. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 95 of 142 hydroxychloroquine and lopinavir/ritonavir). The indirect evidence suggesting a reduction in mortality with ivermectin is driven almost entirely by one study which is at high risk of bias (117) due to a lack of detailed description of blinding or randomization and the lack of a publicly available study protocol (figure not shown). Fig. 3. Forest plot demonstrating direct comparison of ivermectin versus standard of care for mortality with subgroup analysis by risk of bias IV: inverse variance. In addition to concerns related to risk of bias, for the outcome of mortality, there are very serious concerns related to imprecision. According to GRADE, imprecision is evaluated based on both a confidence interval approach and an evaluation of information size (event number), ensuring there is adequate information on which to make informed judgments (126). In this case, despite confidence intervals that suggest benefit with ivermectin, the information size is very low. For mortality (and ignoring the concerns related to risk of bias discussed above), there were nine deaths across all 511 patients randomized to ivermectin (1.76%) and 22 deaths across all 404 patients randomized to standard of care (5.45%). This is an extremely small number of events on which to base conclusions, and far below the optimal information size. In fact, performing a theoretical exercise in which a change of three events (deaths) is made from those randomized to standard of care to those randomized to ivermectin eliminates any statistical significance, a finding that suggests that results could reasonably be due to chance alone. Furthermore, the evidence informing this comparison is from multiple small trials, adding to the risk of unrecognized imbalances in study arms. Given the strong likelihood that chance may be playing a role in the observed findings, the panel believed there was very serious imprecision further lowering the overall certainty in findings. This combination of serious risk of bias and very serious imprecision contributed to very low certainty of evidence for mortality despite a point estimate and confidence interval that appear to suggest benefit with ivermectin. As a result, the panel concluded that the effect of ivermectin on mortality is uncertain. Similar considerations were applied to the other critical outcomes including mechanical ventilation, hospital admission, and duration of hospitalization and resulted in very low certainty for these outcomes as well. Subgroup analyses We conducted subgroup analysis only for effect by ivermectin dose and the panel did not find any evidence of a subgroup effect (see Research evidence). A lack of within-trial comparisons prevented subgroup analyses by age or disease severity. Therefore, the panel did not make any subgroup recommendation for this drug. In other words, the recommendation against ivermectin except in the context of clinical trials is applicable across disease severity, age groups, and all dose regimens of ivermectin. Applicability None of the included RCTs enrolled children under 15, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with ivermectin. There were similar considerations for pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently to other adults. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 96 of 142 Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Ivermectin Comparator: Standard care Summary Evidence summary The LNMA on ivermectin was based on 16 RCTs and 2407 participants. Of the included studies, 75% examined patients with non-severe disease and 25% included both severe and non-severe patients. A number of the included studies did not report on our outcomes of interest. Of the studies, 25% were published in peer-reviewed journals, 44% were available as preprints and 31% were completed but unpublished (see Table on trial characteristics). We excluded a number of quasi-RCTs (127)(128)(129)(130). The GRADE Summary of Findings table shows the relative and absolute effects of ivermectin compared to usual care for the outcomes of interest in patients with COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The NMA team performed subgroup analyses which could result in distinct recommendations by subgroups. From the available data, subgroup analyses were only possible by dose of ivermectin and considering the outcomes of mortality, mechanical ventilation, admission to hospital, and adverse events leading to drug discontinuation. The ivermectin dose subgroup analyses were performed from the direct comparison of ivermectin versus usual care. For these analyses, meta-regression was used to evaluate the effect of cumulative dose as a continuous variable, and further adding a co- variate for single vs multiple dosing regimens. This approach was based on input from the pharmacology experts (led by Professor Andrew Owen) who performed pharmacokinetic simulations across trial doses, and found that cumulative ivermectin dose was expected to correlate with key pharmacokinetic parameters when single- and multiple-dose studies were segregated. It should be noted that the included trials did not directly assess the pharmacokinetics of ivermectin, and our approach was based upon simulations validated where possible against published pharmacokinetics in humans. The panel used a pre-specified framework incorporating the ICEMAN tool to assess the credibility of subgroup findings (110). The GDG panel requested subgroup analyses based on: age (considering children vs younger adults vs older adults [70 years or older]); illness severity (non-severe vs severe vs critical COVID-19); time from onset of symptoms; and use of concomitant medications. However, there was insufficient within-trial data to perform any of these subgroup analyses, based on our pre-specified protocol. The panel recognized that usual care is likely variable between centres and regions, and has evolved over time. However, given all of the data come from RCTs, use of these co-interventions that comprise usual care should be balanced between study patients randomized to either the intervention or usual care arms. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ivermectin Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.19 (CI 95% 0.09 — 0.36) Based on data from 1419 participants in 7 studies. 1 (Randomized controlled) 70 per 1000 Difference: 14 per 1000 56 fewer per 1000 ( CI 95% 63 fewer — 44 fewer ) Very low Due to serious risk of bias and very serious imprecision 2 The effect of ivermectin on mortality is uncertain. Mechanical ventilation Odds ratio 0.51 (CI 95% 0.12 — 1.77) Based on data from 687 participants in 5 studies. (Randomized controlled) 20 per 1000 Difference: 10 per 1000 10 fewer per 1000 ( CI 95% 18 fewer Very low Due to very serious imprecision and publication bias 3 The effect of ivermectin on mechanical ventilation is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 97 of 142 — 15 more ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ivermectin Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Control arm of reference used for intervention. We elected to use the control arm of the WHO SOLIDARITY trial, reflecting usual care across countries participating in the trial. 2. Risk of bias: serious. The large trial contributing most of the effect estimate was driven by studies that were not blinded. Viral clearance 7 days Odds ratio 1.62 (CI 95% 0.95 — 2.86) Based on data from 625 participants in 6 studies. (Randomized controlled) 500 per 1000 Difference: 618 per 1000 118 more per 1000 ( CI 95% 13 fewer — 241 more ) Low Due to serious inconsistency and imprecision 4 Ivermectin may increase or have no effect on viral clearance. Hospital admission (outpatients only) Odds ratio 0.36 (CI 95% 0.08 — 1.48) Based on data from 398 participants in 1 study. (Randomized controlled) 50 per 1000 Difference: 18 per 1000 32 fewer per 1000 ( CI 95% 47 fewer — 23 more ) Very low Due to extremely serious imprecision 5 The effect of ivermectin on hospital admission is uncertain. Serious adverse events leading to discontinuation Odds ratio 3.07 (CI 95% 0.77 — 12.09) Based on data from 584 participants in 3 studies. (Randomized controlled) 9 per 1000 Difference: 27 per 1000 18 more per 1000 ( CI 95% 0 more — 89 more ) Low Due to very serious imprecision 6 Ivermectin may increase the risk of serious adverse events leading to drug discontinuation. Time to clinical improvement Measured by: days Lower better Based on data from 633 participants in 2 studies. (Randomized controlled) 11 days (Mean) Difference: 10.5 days (Mean) MD 0.5 fewer ( CI 95% 1.7 fewer — 1.1 more ) Low Due to very serious imprecision 7 Ivermectin may have little or no difference on time to clinical improvement. Duration of hospitalization Measured by: days Lower better Based on data from 252 participants in 3 studies. (Randomized controlled) 12.8 days (Mean) Difference: 11.7 days (Mean) MD 1.1 fewer ( CI 95% 2.3 fewer — 0.1 more ) Very low Due to serious imprecision, inconsistency and serious risk of bias 8 The effect of ivermectin on hospital length of stay is uncertain. Time to viral clearance Measured by: days Lower better Based on data from 559 participants in 4 studies. (Randomized controlled) 7.3 days (Mean) Difference: 5.7 days (Mean) MD 1.6 fewer ( CI 95% 4.1 fewer — 3 more ) Very low Due to very serious imprecision and serious risk of bias 9 We are uncertain whether ivermectin improves or worsens time to viral clearance. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 98 of 142 6.12.1 Mechanism of action Ivermectin is an antiparasitic agent that interferes with nerve and muscle function of helminths through binding glutamate-gated chloride channels (131). Based on in vitro experiments, some have postulated that ivermectin may have a direct antiviral effect against SARS-CoV-2. However, in humans the concentrations needed for in vitro inhibition are unlikely to be achieved by the doses proposed for COVID-19 (132)(133)(134). Ivermectin had no impact on SARS-CoV-2 viral RNA in the Syrian golden hamster model of SARS-CoV-2 infection (135). The proposed mechanism remains unclear: multiple targets have been proposed based upon either analogy to other viruses with very different life cycles, or, like several hundred other candidates, simulations indicating molecular docking with multiple viral targets including spike, RdRp and 3CLpro (136)(137)(138)(139)(140). No direct evidence for any mechanism of antiviral action against SARS-CoV-2 currently exists. Some have proposed, based predominantly upon research in other indications, that ivermectin has an immunomodulatory effect, but again the mechanism remains unclear. Historical data showed that ivermectin improved survival in mice given a lethal dose of lipopolysaccharide (141), and has benefits in murine models of atopic dermatitis and allergic asthma (142)(143). For SARS- CoV-2, one hypothesis suggests immunomodulation mediated by allosteric modulation of the alpha-7 nicotinic acetylcholine receptor (indirectly by modulating the activity of ligands of the receptor). Although investigators have demonstrated this action in vitro, concentrations used in these experiments have been even higher than those required for an antiviral effect (144), and therefore very unlikely to be achieved in humans. In the Syrian golden hamster model of SARS-CoV-2 infection, ivermectin resulted in some changes in pulmonary immune phenotype consistent with allosteric modulation of the alpha-7 nicotinic acetylcholine receptor (135). However, ivermectin did not appear to rescue body weight loss which is a hallmark of disease in this model, and drug concentrations were not measured to extrapolate to those achieved in humans. Taken together, there remains great uncertainty regarding the relevance of any immunomodulatory or anti-inflammatory action of ivermectin. 6.13 Hydroxychloroquine (published 17 December 2020) Imprecision: very serious. The number of total events was very small. 3. Imprecision: very serious. Very few events and credible intervals that include both important benefit and harm. Publication bias: serious. 4. Inconsistency: serious. The point estimates varied widely and credible intervals do not substantially overlap. Imprecision: serious. Credible interval includes no effect. 5. Imprecision: extremely serious. Credible interval includes important benefit and harm. 6. Imprecision: very serious. Credible interval includes little to no difference. 7. Imprecision: very serious. 8. Risk of bias: serious. Result driven by one study that was not blinded. Inconsistency: serious. Despite overlapping confidence intervals, point estimates discrepant. Imprecision: serious. Credible intervals include no difference. 9. Risk of bias: serious. Concerns around risk of bias. Imprecision: very serious. Credible interval includes important benefit and important harm. Info Box The recommendation concerning hydroxychloroquine was published 17 December 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLIDARITY trial on 15 October 2020, reporting results on treatment with hydroxychloroquine, remdesivir and lopinavir/ritonavir in hospitalized patients with COVID-19 (15). No changes were made to the hydroxychloroquine recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 99 of 142 For patients with COVID-19, regardless of disease severity Practical Info The GDG made a strong recommendation against using hydroxychloroquine or chloroquine for treatment of patients with COVID-19. The use of hydroxychloroquine may preclude the use of other important drugs that also prolong the QT interval, such as azithromycin and fluoroquinolones. Concomitant use of drugs that prolong the QT interval should be done with extreme caution. Evidence To Decision Strong recommendation against We recommend not to use hydroxychloroquine or chloroquine (strong recommendation against). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. Hydroxychloroquine and chloroquine probably do not reduce mortality or mechanical ventilation and may not reduce duration of hospitalization. The evidence does not exclude the potential for a small increased risk of death and mechanical ventilation with hydroxychloroquine. The effect on other less important outcomes, including time to symptom resolution, admission to hospital, and duration of mechanical ventilation, remains uncertain. Hydroxychloroquine may increase the risk of diarrhoea and nausea/vomiting; a finding consistent with evidence from its use in other conditions. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension and acute kidney injury, especially in settings where health care resources are limited. Whether or not and to what degree hydroxychloroquine increases the risk of cardiac toxicity, including life-threatening arrhythmias, is uncertain. Subgroup analyses indicated no effect modification based on severity of illness (comparing either critical vs severe/non- severe or non-severe vs critical/severe) or age (comparing those aged < 70 years vs older). Further, the cumulative dose and predicted Day 3 serum trough concentrations did not modify the effect for any outcome. Therefore, we assumed similar effects in all subgroups. We also reviewed evidence comparing the use of hydroxychloroquine plus azithromycin vs hydroxychloroquine alone. There was no evidence that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome (very low certainty). Benefits and harms For the key outcomes of mortality and mechanical ventilation, the panel considered the evidence to be of moderate certainty. There were residual concerns about lack of blinding in the largest trials and the imprecision. For example, the credible interval around the pooled effect leaves open the possibility of a very small reduction in mortality. The quality of evidence was low for diarrhoea and nausea/vomiting because of lack of blinding in many of the trials and because the total number of patients enrolled in trials reporting these outcomes was smaller than the optimal information size (although the credible interval laid entirely on the side of harm for both outcomes). For all other outcomes, the certainty of the evidence was low or very low. The primary concerns with the data were imprecision (credible intervals included both important benefit and important harm) as well as risk of bias (lack of blinding). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would not want to receive hydroxychloroquine given the evidence suggesting there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and vomiting. The panel did not expect there would be much variation in values and preferences between patients when it came to this intervention. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 100 of 142 Justification When moving from evidence to the strong recommendation against the use of hydroxychloroquine or chloroquine for patients with COVID-19, the panel emphasized the moderate certainty evidence of probably no reduction in mortality or need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased nausea and diarrhoea. The GDG did not anticipate important variability in patient values and preferences, and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity (see summary of these factors under Evidence to decision). Subgroup analyses The panel did not find any evidence of a subgroup effect across patients with different levels of disease severity, between adults and older adults, and by different doses, and therefore did not make any subgroup recommendation for this drug. In other words, the strong recommendation is applicable across disease severity, age groups, and all doses and dose schedules of hydroxychloroquine. The trials included patients from around the world, with all disease severities, and treated in different settings (outpatient and inpatient). Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease course. The GDG panel therefore felt that the evidence applies to all patients with COVID-19. Applicability Special populations None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with hydroxychloroquine. There were similar considerations in regards to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. Hydroxychloroquine crosses the placental barrier and there are concerns that it may lead to retinal damage in neonates. Although hydroxychloroquine has been used in pregnant women with systemic autoimmune diseases, such as systemic lupus erythematosus, pregnant women may have even more reasons than other patients to be reluctant to use hydroxychloroquine for COVID-19. In combination with azithromycin There was no evidence from the NMA that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome. As there were no trial data suggesting that azithromycin favourably modifies the effect of hydroxychloroquine, the recommendation against hydroxychloroquine and chloroquine applies to patients whether or not they are concomitantly receiving azithromycin. Uncertainties Please see end of document for residual uncertainties (Section 9). The GDG panel felt that it was unlikely future studies would identify a subgroup of patients that are likely to benefit from hydroxychloroquine or chloroquine. Hydroxychloroquine and chloroquine are relatively inexpensive compared with other drugs used for COVID-19 and are already widely available, including in low-income settings. Despite this, the panel felt that almost all patients would choose not to use hydroxychloroquine or chloroquine because the harms outweigh the benefits. Although the cost may be low per patient, the GDG panel raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe COVID-19 and other supportive care interventions. Resources and other considerations Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Hydroxychloroquine Comparator: Standard care Summary Evidence summary Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 101 of 142 The LNMA on hydroxychloroquine was based on 30 RCTs with 10 921 participants, providing relative estimates of effect for patient-important outcomes (see Table). Five of the trials (414 total participants) randomized some patients to chloroquine. The GRADE Summary of Findings table shows the relative and absolute effects of hydroxychloroquine compared with usual care for the outcomes of interest in patients with COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis For hydroxychloroquine, the GDG panel requested subgroup analyses based on age (considering children vs younger adults [e.g. < 70 years] vs older adults [e.g. 70 years or older]), illness severity (non-severe vs severe vs critical COVID-19) and based on whether or not it was co-administered with azithromycin. The panel also requested a subgroup analysis based on high dose vs low dose hydroxychloroquine. A categorical approach to hydroxychloroquine dosing proved impossible because the trials used varying loading doses, continuation doses and durations. Therefore, in collaboration with a pharmacology expert (Professor Andrew Owen), we modelled the expected serum concentrations over time. We hypothesized that higher trough concentrations early in the treatment course (e.g. trough concentration on Day 3) might be more effective than lower early trough concentrations. We also hypothesized that higher maximum serum concentrations (e.g. peak concentration on the last day) might result in higher risk of adverse effects than lower maximum serum concentrations. In our pharmacokinetic model, the cumulative dose was highly correlated with all measures of serum concentrations on Day 3 and the final day of treatment, and therefore we decided to use cumulative dose as the primary analysis. Day 3 trough concentration was least strongly correlated with total cumulative dose (R2 = 0.376) and therefore we performed a sensitivity subgroup analysis with predicted Day 3 trough concentrations for efficacy outcomes. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 1.11 (CI 95% 0.95 — 1.31) Based on data from 10 859 participants in 29 studies. 1 (Randomized controlled) 106 per 1000 Difference: 116 per 1000 10 more per 1000 ( CI 95% 5 fewer — 28 more ) Moderate Due to borderline risk of bias and imprecision 2 Hydroxychloroquine probably does not reduce mortality. Mechanical ventilation Odds ratio 1.2 (CI 95% 0.83 — 1.81) Based on data from 6379 participants in 5 studies. (Randomized controlled) 105 per 1000 Difference: 123 per 1000 18 more per 1000 ( CI 95% 16 fewer — 70 more ) Moderate Due to borderline risk of bias and serious imprecision 3 Hydroxychloroquine probably does not reduce mechanical ventilation. Viral clearance 7 days Odds ratio 1.08 (CI 95% 0.25 — 4.78) Based on data from 280 participants in 4 studies. 4 (Randomized controlled) 483 per 1000 Difference: 502 per 1000 19 more per 1000 ( CI 95% 294 fewer — 334 more ) Very low Due to very serious imprecision 5 The effect of hydroxychloroquine on viral clearance is very uncertain. Admission to hospital Odds ratio 0.39 (CI 95% 0.12 — 1.28) Based on data from 465 participants in 1 study. (Randomized controlled) 47 per 1000 19 per 1000 Very low Due to very serious imprecision and serious indirectness 6 The effect of hydroxychloroquine on admission to hospital is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 102 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary ( CI 95% 41 fewer — 12 more ) Cardiac toxicity Based on data from 3287 participants in 7 studies. (Randomized controlled) 46 per 1000 Difference: 56 per 1000 10 more per 1000 ( CI 95% 0 more — 30 more ) Very low Due to serious imprecision, risk of bias, and indirectness 7 The effect of hydroxychloroquine on cardiac toxicity is uncertain. Diarrhoea Odds ratio 1.95 (CI 95% 1.4 — 2.73) Based on data from 979 participants in 6 studies. (Randomized controlled) 149 per 1000 Difference: 255 per 1000 106 more per 1000 ( CI 95% 48 more — 174 more ) Low Due to serious imprecision and risk of bias 8 Hydroxychloroquine may increase the risk of diarrhoea. Nausea/ vomiting Odds ratio 1.74 (CI 95% 1.26 — 2.41) Based on data from 1429 participants in 7 studies. (Randomized controlled) 99 per 1000 Difference: 161 per 1000 62 more per 1000 ( CI 95% 23 more — 110 more ) Low Due to serious imprecision and serious risk of bias 9 Hydroxychloroquine may increase the risk of nausea and vomiting. Delirium Odds ratio 1.59 (CI 95% 0.77 — 3.28) Based on data from 423 participants in 1 study. (Randomized controlled) 62 per 1000 Difference: 95 per 1000 33 more per 1000 ( CI 95% 14 fewer — 116 more ) Very low Due to very serious imprecision and serious indirectness 10 The effect of hydroxychloroquine on delirium is uncertain. Time to clinical improvement Lower better Based on data from 479 participants in 5 studies. (Randomized controlled) 11 days (Mean) Difference: 9 days (Mean) MD 2 fewer ( CI 95% 4 fewer — 0.1 more ) Very low Due to serious risk of bias, imprecision, and indirectness 11 The effect of hydroxychloroquine on time to clinical improvement is uncertain. Duration of hospitalization Lower better Based on data from 5534 participants in 5 studies. (Randomized controlled) 12.8 days (Mean) Difference: 12.9 days (Mean) MD 0.1 more ( CI 95% 1.9 fewer — 2 more ) Low Due to serious imprecision and serious risk of bias 12 Hydroxychloroquine may have no effect on duration of hospitalization. Time to viral clearance Lower better Based on data from 440 participants in 5 studies. (Randomized controlled) 9.7 days (Mean) 10.6 days (Mean) Very low Due to serious risk of bias and very serious imprecision 13 The effect of hydroxychloroquine on time to viral clearance is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 103 of 142 Difference: 28 fewer per 1000 6.14 Lopinavir-ritonavir (published 17 December 2020) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19. 2. Imprecision: serious. The 95% CI crosses the minimally important difference (2% reduction in mortality). . 3. Imprecision: serious. Wide confidence intervals. 4. Systematic review. We used the median event rate for all patients randomized to usual care across included studies. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [1], 5. Imprecision: very serious. Wide confidence intervals. 6. Indirectness: serious. Imprecision: very serious. 7. Risk of bias: serious. Unblinded studies -> cardiac toxicity differential detection. Indirectness: serious. Studies measured serious cardiac toxicity differently. Imprecision: serious. 8. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. OIS not met. Upgrade: large magnitude of effect. 9. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. OIS not met. Upgrade: large magnitude of effect. 10. Indirectness: serious. This outcome was not collected systematically and the definition of delirium was not specified. Imprecision: very serious. 11. Risk of bias: serious. Indirectness: serious. Studies measured clinical improvement differently. Imprecision: serious. 12. Risk of bias: serious. Imprecision: serious. Wide confidence intervals. 13. Risk of bias: serious. Imprecision: very serious. 14. Imprecision: extremely serious. fewer — 4.8 more ) Adverse events leading to drug discontinuation Based on data from 210 participants in 3 studies. (Randomized controlled) Two of 108 patients randomized to hydroxychloroquine discontinued treatment because of adverse effects. None of 102 patients did so in the placebo/standard care group. Very low Due to extremely serious imprecision 14 The effect of hydroxychloroquine on adverse events leading to drug discontinuation is uncertain. Info Box The recommendation concerning lopinavir-ritonavir was published 17 December 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLIDARITY trial on 15 October 2020, reporting results on treatment with lopinavir-ritonavirsivir, remdesivir and hydroxychloroquine in hospitalized patients with COVID-19 (15). No changes were made to the lopinavir-ritonavir recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 104 of 142 Difference: MD 0.7 fewer ( CI 95% 4.3 For patients with COVID-19, regardless of disease severity Evidence To Decision Justification When moving from evidence to the strong recommendation against the use of lopinavir-ritonavir for patients with COVID-19, the panel emphasized the moderate certainty evidence of probably no reduction in mortality or need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased nausea and diarrhoea. The GDG did not anticipate important variability in patient values and preferences, and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity would not alter the recommendation (see summary of these factors under Evidence to Decision). Strong recommendation against We recommend not to use lopinavir-ritonavir (strong recommendation against). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. The GDG panel found a lack of evidence that lopinavir-ritonavir improved outcomes that matter to patients such as reduced mortality, need for mechanical ventilation, time to clinical improvement and others. For mortality and need for mechanical ventilation this was based on moderate certainty evidence, for the other outcomes low or very low certainty evidence. There was low certainty evidence that lopinavir-ritonavir may increase the risk of diarrhoea and nausea and vomiting, a finding consistent with the indirect evidence evaluating its use in patients with HIV. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension and acute kidney injury, especially in settings where health care resources are limited. There was an uncertain effect on viral clearance and acute kidney injury. Subgroup analysis indicated no effect modification based on severity of illness (comparing either critical vs severe/non- severe or non-severe vs critical/severe) or age (comparing those aged < 70 years versus those 70 years and older). As there was no evidence of a statistical subgroup effect, we did not formally evaluate using the ICEMAN tool. Benefits and harms The evidence is based on a linked systematic review and NMA of seven RCTs; pooling data from 7429 patients hospitalized with various severities of COVID-19 and variably reporting the outcomes of interest to the guideline panel (1). The panel agreed that there was moderate certainty for mortality and need for mechanical ventilation, low certainty for diarrhoea, nausea and duration of hospitalization and very low certainty in the estimates of effect for viral clearance, acute kidney injury and time to clinical improvement. Most outcomes were lowered for risk of bias and imprecision (wide confidence intervals which do not exclude important benefit or harm). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would not want to receive lopinavir-ritonavir given the evidence suggested there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and vomiting. The panel did not expect there would be much variation in values and preferences between patients when it came to this intervention. Values and preferences Although the cost of lopinavir-ritonavir is not as high as some other investigational drugs for COVID-19, and the drug is generally available in most health care settings, the GDG raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe COVID-19. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 105 of 142 Subgroup analysis The panel did not find any evidence of a subgroup effect across patients with different levels of disease severity, or between adults and older adults and therefore did not make any subgroup recommendation for this drug. Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease course. The strong recommendation is applicable across disease severity and age groups. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with lopinavir-ritonavir. There were similar considerations in regards to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. In patients using lopinavir-ritonavir for HIV infection, it should generally be continued while receiving care for COVID-19. Uncertainties Please see end of document for residual uncertainties (Section 9). The GDG panel felt that it was unlikely future studies would identify a subgroup of patients that are likely to benefit from lopinavir-ritonavir. Additional considerations In patients who have undiagnosed or untreated HIV, use of lopinavir-ritonavir alone may promote HIV resistance to important antiretrovirals. Widespread use of lopinavir-ritonavir for COVID-19 may cause drug shortages for people living with HIV. Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Lopinavir-ritonavir Comparator: Standard care Summary Evidence summary The LNMA on lopinavir-ritonavir was based on 7 RCTs with 7429 participants. Of note, none of the included studies enrolled children or adolescents under the age of 19 years old (see Table). The GRADE Summary of Findings table shows the relative and absolute effects of lopinavir-ritonavir compared with usual care for the outcomes of interest in patients with COVID-19 across all disease severities, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis For lopinavir-ritonavir, the GDG panel requested subgroup analyses based on age (considering children vs younger adults [e.g. under 70 years] vs older adults [e.g. 70 years or older]), and illness severity (non-severe vs severe vs critical COVID-19). The GDG discussed other potential subgroups of interest including time from onset of symptoms until initiation of therapy and concomitant medications, but recognized that these analyses would not be possible without access to individual participant data and/or more detailed reporting from the individual trials. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 1 (CI 95% 0.82 — 1.2) Based on data from 8061 participants in 4 studies. 1 (Randomized controlled) 106 per 1000 Difference: 106 per 1000 0 fewer per 1000 ( CI 95% 17 fewer — 19 more ) Moderate Due to borderline risk of bias and imprecision 2 Lopinavir-ritonavir probably has no effect on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 106 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation Relative risk 1.16 (CI 95% 0.98 — 1.36) Based on data from 7579 participants in 3 studies. (Randomized controlled) 105 per 1000 Difference: 122 per 1000 17 more per 1000 ( CI 95% 2 fewer — 38 more ) Moderate Due to borderline risk of bias and imprecision 3 Lopinavir-ritonavir probably does not reduce mechanical ventilation. Viral clearance Odds ratio 0.35 (CI 95% 0.04 — 1.97) Based on data from 171 participants in 2 studies. 4 (Randomized controlled) 483 per 1000 Difference: 246 per 1000 237 fewer per 1000 ( CI 95% 447 fewer — 165 more ) Low Due to very serious imprecision 5 The effects of lopinavir- ritonavir on viral clearance is very uncertain. Acute kidney injury Based on data from 259 participants in 2 studies. (Randomized controlled) 45 per 1000 Difference: 25 per 1000 20 fewer per 1000 ( CI 95% 70 fewer — 20 more ) Very low Due to serious risk of bias and very serious imprecision 6 The effect of lopinavir- ritonavir on acute kidney injury is uncertain. Diarrhoea Odds ratio 4.28 (CI 95% 1.99 — 9.18) Based on data from 370 participants in 4 studies. (Randomized controlled) 67 per 1000 Difference: 235 per 1000 168 more per 1000 ( CI 95% 58 more — 330 more ) Moderate Due to serious risk of bias and imprecision; upgraded due to large magnitude of effect 7 Lopinavir-ritonavir may increase the risk of diarrhoea. Nausea/ vomiting Based on data from 370 participants in 4 studies. (Randomized controlled) 17 per 1000 Difference: 177 per 1000 160 more per 1000 ( CI 95% 100 more — 210 more ) Moderate Due to serious risk of bias and imprecision 8 Lopinavir-ritonavir may increase the risk of nausea/vomiting. Time to clinical improvement Lower better Based on data from 199 participants in 1 study. (Randomized controlled) 11 days (Mean) Difference: 10 days (Mean) MD 1 fewer ( CI 95% 4.1 fewer — 3.2 more ) Very low Due to serious risk of bias and very serious imprecision 9 The effect of lopinavir- ritonavir improves on time to clinical improvement is very uncertain. Duration of hospitalization Lower better Based on data from 5239 participants in 2 12.8 days (Mean) 12.5 days (Mean) Low Due to serious risk of bias and imprecision 10 Lopinavir-ritonavir may have no effect on duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 107 of 142 6.15 Systemic corticosteroids (published 2 September 2020) For patients with severe or critical COVID-19 Practical Info Route: Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioavailability of dexamethasone is very high (that is, similar concentrations are achieved in plasma after oral and intravenous intake), critically ill patients may be unable to absorb any nutrients or medications due to intestinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Primary study[15]. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19. Supporting references: [1], 2. Imprecision: serious. The 95% CI crosses the minimally important difference (2% reduction in mortality). 3. Imprecision: serious. Wide confidence intervals. 4. Systematic review. Baseline/comparator: Control arm of reference used for intervention. We used the median event rate for all patients randomized to usual care across included studies. Supporting references: [1], 5. Imprecision: very serious. Wide confidence intervals. 6. Risk of bias: serious. Imprecision: very serious. Wide confidence intervals. 7. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. Few patients and events. Upgrade: large magnitude of effect. 8. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. Few patients and events. Upgrade: large magnitude of effect. 9. Risk of bias: serious. Imprecision: very serious. Wide confidence intervals, low number of patients. 10. Risk of bias: serious. Imprecision: serious. Wide confidence intervals. studies. (Randomized controlled) Difference: MD 0.3 lower ( CI 95% 3 lower — 2.5 higher ) Info Box The recommendations for corticosteroids were first published as WHO living guidelines 2 September 2020, and as BMJ Rapid Recommendations 5 September 2020. It followed the publication of the preliminary report of the RECOVERY trial, later published as a peer-reviewed paper (14). No changes were made to the corticosteroids recommendations in this eleventh version of the guideline. Whereas the recommendations remain unchanged, the evidence summary for corticosteroids in patients with COVID-19 was updated before the sixth iteration of this living guideline. The baseline risk estimates for mortality are now based on the WHO SOLIDARITY trial (as for other drugs in this guideline) (15) rather than the initial ISARIC cohort study (149) that likely overestimates current mortality risks at the global level. The update was also needed to inform the baseline risk for mortality in the evidence summary informing the strong recommendation for IL-6 receptor blockers, in addition to standard of care for patients with severe or critical COVID-19, where corticosteroids provide a relative reduction in mortality by 21%. Strong recommendation for We recommend treatment with systemic corticosteroids (strong recommendation for). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 108 of 142 Duration: While more patients received corticosteroids in the form of dexamethasone 6 mg daily for up to 10 days, the total duration of regimens evaluated in the seven trials varied between 5 and 14 days, and treatment was generally discontinued at hospital discharge (that is, the duration of treatment could be less than the duration stipulated in the protocols). Dose: The once daily dexamethasone formulation may increase adherence. A dose of 6 mg of dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg of hydrocortisone (that is, 50 mg every 8 hours), 40 mg of prednisone, or 32 mg of methylprednisolone (8 mg every 6 hours or 16 mg every 12 hours). Monitoring: It would be prudent to monitor glucose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to have diabetes. Timing: The timing of therapy from onset of symptoms was discussed by the panel. The RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 days or more after symptom onset may be more beneficial than treatment initiated within 7 days of symptom onset. A post hoc subgroup analysis within the PMA did not support this hypothesis. While some panel members believed that postponing systemic corticosteroids until after viral replication is contained by the immune system may be reasonable, many noted that, in practice, it is often impossible to ascertain symptom onset and that signs of severity often appear late (that is, denote a co-linearity between severity and timing). The panel concluded that, given the evidence, it was preferable to err on the side of administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 days of symptoms onset) and to err on the side of not giving corticosteroids when treating patients with non-severe disease (even if after 7 days of symptoms onset). Evidence To Decision Panel members who voted for a conditional recommendation argued that the trials evaluating systemic corticosteroids for COVID-19 reported limited information regarding potential harm. Between the two panel meetings, indirect evidence regarding the potential harmful effects of systemic corticosteroids from studies in sepsis, ARDS and community-acquired pneumonia (CAP) was added to the summary of findings table (150)(151). While generally of low certainty, these data were reassuring and suggested that corticosteroids are not associated with an increased risk of adverse events, beyond likely increasing the incidence of hyperglycaemia (moderate certainty evidence; absolute effect estimate 46 more per 1000 patients, 95% CI: 23 more to 72 more) and hypernatraemia (moderate certainty evidence; 26 more per 1000 patients, 95% CI: 13 more to 41 more). Panel members also noted that, given the expected effect of systemic corticosteroids on mortality, most patients would not refuse this intervention to avoid adverse events believed to be markedly less important to most patients than death. In contrast with new agents proposed for COVID-19, clinicians have a vast experience of systemic corticosteroids and the panel was reassured by their overall safety profile. Moreover, the panel was confident that clinicians using these guidelines would be aware of additional potential side-effects and contraindications to systemic corticosteroid therapy, which may vary geographically in function of endemic microbiological flora. Notwithstanding, clinicians should exercise caution in use of corticosteroids in patients with diabetes or underlying immunocompromise. Ultimately, the panel made its recommendation on the basis of the moderate certainty evidence of a 28-day mortality reduction of 8.7% in the critically ill and 6.7% in patients with severe COVID-19 who were not critically ill, respectively. In the fifth iteration of this living guideline, mortality baseline risk estimates were updated based on the WHO SOLIDARITY trial, considered to represent the best source of prognosis across countries facing the COVID-19 pandemic. This resulted in an overall 3.3% reduction in 28-day mortality for patients with severe or critical COVID-19, still with moderate certainty evidence and considered by the panel to represent a clear benefit to patients, with no impact on the established recommendations. Benefits and harms The panel took an individual patient perspective to values and preferences but, given the burden of the pandemic for health care systems globally, also placed a high value on resource allocation and equity. The benefits of corticosteroids on mortality was deemed of critical importance to patients, with little or no anticipated variability in their preference to be offered treatment if severely ill from COVID-19. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 109 of 142 Justification This recommendation was achieved after a vote, which concerned the strength of the recommendation in favour of systemic corticosteroids. Of the 23 voting panel members, 19 (83%) voted in favour of a strong recommendation, and 4 (17%) voted in favour of a conditional recommendation. The reasons for the four cautionary votes, which were shared by some panel members who voted in favour of a strong recommendation, are summarized below. Applicability Panel members who voted for a conditional recommendation argued that many patients who were potentially eligible for the RECOVERY trial were excluded from participating in the evaluation of corticosteroids by their treating clinicians and that without detailed information on the characteristics of excluded patients, this precluded, in their opinion, a strong recommendation. Other panel members felt that such a proportion of excluded patients was the norm rather than the exception in pragmatic trials and that, while detailed information on the reasons for excluding patients were not collected, the main reasons for refusing to offer participation in the trial were likely related to safety concerns of stopping corticosteroids in patients with a clear indication for corticosteroids (confirmed as per personal communication from the RECOVERY Principal Investigator). Panel members noted that there are few absolute contraindications to a 7–10 day course of corticosteroid therapy, that recommendations are intended for the average patient population, and that it is understood that even strong recommendations should not be applied to patients in whom the intervention is contraindicated as determined by the treating clinician. Eventually, the panel concluded that this recommendation applies to patients with severe and critical COVID-19 regardless of hospitalization status. The underlying assumption is that these patients would be treated in hospitals and receive respiratory support in the form of oxygen; non-invasive or invasive ventilation if these options were available. Following GRADE guidance, in making a strong recommendation, the panel has inferred that all or almost all fully informed patients with severe COVID-19 would choose to take systemic corticosteroids. It is understood that even in the context of a strong recommendation, the intervention may be contraindicated for certain patients. Absolute contraindications for 7–10 day courses of systemic corticosteroid therapy are rare. In considering potential contraindications, clinicians must determine if they warrant depriving a patient of a potentially life-saving therapy. The applicability of the recommendation is less clear for populations that were under-represented in the considered trials, such as children, patients with tuberculosis, and those who are immunocompromised. Notwithstanding, clinicians will also consider the risk of depriving these patients of potentially life-saving therapy. In contrast, the panel concluded that the recommendation should definitely be applied to certain patients who were not included in the trials, such as patients with severe and critical COVID-19 who could not be hospitalized or receive oxygen because of resource limitations. The recommendation does not apply to the following uses of corticosteroids: transdermal or inhaled administration, high-dose or long-term regimens, or prophylaxis. Resource implications, feasibility, equity and human rights In this guideline, the panel took an individual patient perspective, but also placed a high value on resource allocation. In such a perspective, attention is paid to the opportunity cost associated with the widespread provision of therapies for COVID-19. In contrast to other candidate treatments for COVID-19 that, generally, are expensive, often unlicensed, difficult to obtain and require advanced medical infrastructure, systemic corticosteroids are low cost, easy to administer, and readily available globally (152). Dexamethasone and prednisolone are among the most commonly listed medicines in national essential medicines lists; listed by 95% of countries. Dexamethasone was first listed by WHO as an essential medicine in 1977, while prednisolone was listed 2 years later (153). Accordingly, systemic corticosteroids are among a relatively small number of interventions for COVID-19 that have the potential to reduce inequities and improve equity in health. Those considerations influenced the strength of this recommendation. Acceptability The ease of administration, the relatively short duration of a course of systemic corticosteroid therapy, and the generally benign safety profile of systemic corticosteroids for up to 7–10 days led the panel to conclude that the acceptability of this intervention was high. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 110 of 142 Clinical Question/ PICO Population: Patients with severe or critical COVID-19 (updated baseline mortality risk) Intervention: Systemic corticosteroids Comparator: Standard care Summary Evidence summary This guideline was triggered on 22 June 2020 by the publication of the preliminary report of the RECOVERY trial, later published as a peer-reviewed paper (14). Corticosteroids are listed in the WHO Model List of Essential Medicines, readily available globally at a low cost, and of considerable interest to all stakeholder groups. The guideline panel was informed by combining two meta-analyses which pooled data from eight randomized trials (7184 participants) of systemic corticosteroids for COVID-19 (1)(154). The panel discussions were also informed by two other meta-analyses, which were already published and pooled data about the safety of systemic corticosteroids in distinct but relevant patient populations. The GRADE Summary of Findings table shows the relative and absolute effects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. Below we provide more details about the trials and meta-analysis as well as a subgroup analysis that informed the recommendation. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. On 17 July 2020, the panel reviewed evidence from eight RCTs (7184 patients) evaluating systemic corticosteroids versus usual care in COVID-19. RECOVERY, the largest of the seven trials, from which mortality data were available by subgroup (severe and non-severe), evaluated the effects of dexamethasone 6 mg given once daily (oral or intravenous) for up to 10 days in 6425 hospitalized patients in the United Kingdom (2104 were randomized to dexamethasone and 4321 were randomized to usual care) (14). At the time of randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; 60% were receiving oxygen only (with or without non-invasive ventilation); and 24% were receiving neither. The data from seven other smaller trials included 63 non-critically ill patients and approximately 700 critically ill patients (definitions of critical illness varied across studies). For the latter, patients were enrolled up to 9 June 2020, and approximately four-fifths were invasively mechanically ventilated; approximately half were randomized to receive corticosteroid therapy, and half randomized to no corticosteroid therapy. Corticosteroid regimens included: methylprednisolone 40 mg every 12 hours for 3 days and then 20 mg every 12 hours for 3 days (GLUCOCOVID) (155); dexamethasone 20 mg daily for 5 days followed by 10 mg daily for 5 days (two trials, DEXA-COVID19, CoDEX) (156)(157); hydrocortisone 200 mg daily for 4 to 7 days followed by 100 mg daily for 2 to 4 days and then 50 mg daily for 2 to 3 days (one trial, CAPE-COVID) (158); hydrocortisone 200 mg daily for 7 days (one trial, REMAP- CAP) (16); methylprednisolone 40 mg every 12 hours for 5 days (one trial, Steroids-SARI) (159). Seven of the trials were conducted in individual countries (Brazil, China, Denmark, France, Spain) whilst REMAP-CAP was an international study (recruiting in 14 European countries, Australia, Canada, New Zealand, Saudi Arabia and the United Kingdom). All trials reported mortality 28 days after randomization, except for one trial at 21 days and another at 30 days. Because the mortality data from one trial (GLUCOCOVID, n=63) were not reported by subgroup, the panel reviewed only the data pertaining to the outcome of mechanical ventilation from this trial (155). An additional trial, which randomized hospitalized patients with suspected SARS-CoV-2 infection, published on 12 August 2020 (MetCOVID) (160), was included as a supplement in the PMA publication, as it was registered after the searches of trial registries were performed. The supplement showed that inclusion would not change results other than reduce inconsistency. Subgroup analyses While all other trials evaluated systemic corticosteroids exclusively in critically ill patients, the RECOVERY trial enrolled hospitalized patients with COVID-19. The panel considered the results of a subgroup analysis of the RECOVERY trial suggesting that the relative effects of systemic corticosteroids varied as a function of the level of respiratory support received at randomization. On the basis of the peer-reviewed criteria for credible subgroup effects (110), the panel determined that the subgroup effect was sufficiently credible to warrant separate recommendations for severe and non- severe COVID-19. However, acknowledging that during a pandemic, access to health care may vary considerably over time as well as between different countries, the panel decided against defining patient populations concerned by the recommendations on the basis of access to health interventions (i.e. hospitalization and respiratory support). Thus, the panel attributed the effect modification in the RECOVERY trial to illness severity. The panel also acknowledged the existence of variable definitions for severity and use of respiratory support interventions. The WHO clinical guidance for COVID-19 published on 27 May 2020 (version 3) defined severity of COVID-19 by clinical indicators, but modified the oxygen saturation threshold from 94% to 90%, in order to align with Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 111 of 142 previous WHO guidance (6). See Section 5 for the WHO severity criteria and Infographic for three disease severity groups for which the recommendations apply in practice. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Relative risk 0.79 (CI 95% 0.7 — 0.9) Based on data from 1703 participants in 7 studies. 1 Follow up: 28 days. 160 per 1000 Difference: 126 per 1000 34 fewer per 1000 ( CI 95% 48 fewer — 16 fewer ) Moderate Due to serious risk of bias 2 Systemic corticosteroids probably reduce the risk of 28-day mortality in patients with critical illness due to COVID-19. Need for invasive mechanical ventilation 28 days Relative risk 0.74 (CI 95% 0.59 — 0.93) Based on data from 5481 participants in 2 studies. Follow up: 28 days. 116 per 1000 Difference: 86 per 1000 30 fewer per 1000 ( CI 95% 48 fewer — 8 fewer ) Moderate Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need of mechanical ventilation. Gastrointestinal bleeding Relative risk 1.06 (CI 95% 0.85 — 1.33) Based on data from 5403 participants in 30 studies. 48 per 1000 Difference: 51 per 1000 3 more per 1000 ( CI 95% 7 fewer — 16 more ) Low Due to serious indirectness, Due to serious imprecision 4 Corticosteroids may not increase the risk of gastrointestinal bleeding. Super-infections Relative risk 1.01 (CI 95% 0.9 — 1.13) Based on data from 6027 participants in 32 studies. 186 per 1000 Difference: 188 per 1000 2 more per 1000 ( CI 95% 19 fewer — 24 more ) Low Due to serious indirectness, Due to serious imprecision 5 Corticosteroids may not increase the risk of super-infections. Hyperglycaemia Relative risk 1.16 (CI 95% 1.08 — 1.25) Based on data from 8938 participants in 24 studies. 286 per 1000 Difference: 332 per 1000 46 more per 1000 ( CI 95% 23 more — 72 more ) Moderate Due to serious indirectness 6 Corticosteroids probably increase the risk of hyperglycaemia. Hypernatremia Relative risk 1.64 (CI 95% 1.32 — 2.03) Based on data from 5015 participants in 6 studies. 40 per 1000 Difference: 66 per 1000 26 more per 1000 ( CI 95% 13 more — 41 more ) Moderate Due to serious indirectness 7 Corticosteroids probably increase the risk of hypernatremia. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 112 of 142 For patients with non-severe COVID-19 infection Practical Info With the conditional recommendation against the use of corticosteroids in patients with non-severe COVID-19 the following practical information apply in situations where such treatment is to be considered: Route: Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioavailability of dexamethasone is very high (i.e. similar concentrations are achieved in plasma after oral and intravenous intake), critically ill patients may be unable to absorb any nutrients or medications due to intestinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Primary study[15]. Baseline risk estimate for mortality updated as of May 2021: now from WHO SOLIDARITY (considered the best source) with 14.6% mortality at 28 days in severe and critically ill patients. This estimate adjusted for 50% receiving corticosteroids as standard of care in SOLIDARITY. 2. Risk of bias: serious. Lack of blinding. 3. Risk of bias: serious. Lack of blinding. 4. Indirectness: serious. Imprecision: serious. 5. Indirectness: serious. Imprecision: serious. 6. Indirectness: serious. 7. Indirectness: serious. 8. Indirectness: serious. Imprecision: serious. 9. Indirectness: serious. Imprecision: serious. 10. Risk of bias: serious. Lack of blinding. Imprecision: serious. Confidence interval includes no benefit. Neuromuscular weakness Relative risk 1.09 (CI 95% 0.86 — 1.39) Based on data from 6358 participants in 8 studies. 69 per 1000 Difference: 75 per 1000 6 more per 1000 ( CI 95% 10 fewer — 27 more ) Low Due to serious indirectness, Due to serious imprecision 8 Corticosteroids may not increase the risk of neuromuscular weakness. Neuropsychiatri c effects Relative risk 0.81 (CI 95% 0.41 — 1.63) Based on data from 1813 participants in 7 studies. 35 per 1000 Difference: 28 per 1000 7 fewer per 1000 ( CI 95% 21 fewer — 22 more ) Low Due to serious indirectness, Due to serious imprecision 9 Corticosteroids may not increase the risk of neuropsychiatric effects. Duration of hospitalization Measured by: days Lower better Based on data from 6425 participants in 1 study. (Randomized controlled) 13 days 12 days Low Due to serious risk of bias and serious imprecision 10 Steroids may result in an important reduction in the duration of hospitalizations. Conditional recommendation against We suggest not to use systemic corticosteroids (conditional recommendation against). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 113 of 142 Duration: While more patients received corticosteroids in the form of dexamethasone 6 mg daily for up to 10 days, the total duration of regimens evaluated in the seven trials varied between 5 and 14 days, and treatment was generally discontinued at hospital discharge (i.e. the duration of treatment could be less than the duration stipulated in the protocols). Dose: The once daily dexamethasone formulation may increase adherence. A dose of 6 mg of dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg of hydrocortisone (e.g. 50 mg every 8 hours), or 40 mg of prednisone, or 32 mg of methylprednisolone (e.g. 8 mg every 6 hours or 16 mg every 12 hours). It would be prudent to monitor glucose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to have diabetes. Timing: The timing of therapy from onset of symptoms was discussed by the panel. The RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 days or more after symptom onset may be more beneficial than treatment initiated within 7 days of treatment onset. A post hoc subgroup analysis within the PMA did not support this hypothesis. While some panel members believed that postponing systemic corticosteroids until after viral replication is contained by the immune system may be reasonable, many noted that, in practice, it is often impossible to ascertain symptom onset and that signs of severity frequently appear late (i.e. denote a co-linearity between severity and timing). The panel concluded that, given the evidence, it was preferable to err on the side of administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 days of symptoms onset) and to err on the side of not giving corticosteroids when treating patients with non-severe disease (even if after 7 days of symptoms onset). Other endemic infections that may worsen with corticosteroids should be considered. For example, for Strongyloides stercoralis hyperinfection associated with corticosteroid therapy, diagnosis or empiric treatment may be considered in endemic areas if steroids are used. Evidence To Decision The panel made its recommendation on the basis of low certainty evidence suggesting a potential increase of 3.9% in 28-day mortality among patients with COVID-19 who are not severely ill. The certainty of the evidence for this specific subgroup was downgraded due to serious imprecision (i.e. the evidence does not allow to rule out a mortality reduction) and risk of bias due to lack of blinding. In making a conditional recommendation against the indiscriminate use of systemic corticosteroids, the panel inferred that most fully informed individuals with non-severe illness would not want to receive systemic corticosteroids, but many could want to consider this intervention through shared decision-making with their treating physician (161)(6). Note: WHO recommends antenatal corticosteroid therapy for pregnant women at risk of preterm birth from 24 to 34 weeks’ gestation when there is no clinical evidence of maternal infection, and adequate childbirth and newborn care is available. However, in cases where the woman presents with mild or moderate COVID-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman’s clinical condition, her wishes and that of her family, and available health care resources. Benefits and harms See Benefits and Harms section. Certainty of the Evidence The weak or conditional recommendation was driven by likely variation in patient values and preferences. The panel judged that most individuals with non-severe illness would decline systemic corticosteroids. However, many may want them after shared decision-making with their treating physician. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 114 of 142 Justification This recommendation was achieved by consensus. Applicability This recommendation applies to patients with non-severe disease regardless of their hospitalization status. The panel noted that patients with non-severe COVID-19 would not normally require acute care in hospital or respiratory support, but that in some jurisdictions, these patients may be hospitalized for isolation purposes only, in which case they should not be treated with systemic corticosteroids. The panel concluded that systemic corticosteroids should not be stopped for patients with non-severe COVID-19 who are already treated with systemic corticosteroids for other reasons (e.g. patients with chronic obstructive pulmonary disease or other chronic autoimmune diseases need not discontinue a course of systemic oral corticosteroid). If the clinical condition of patients with non-severe COVID-19 worsens (i.e. increase in respiratory rate, signs of respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation for severe and critical COVID-19). Resource implications, feasibility, equity and human rights The panel also considered that in order to help guarantee access to systemic corticosteroids for patients with severe and critical COVID-19, it is reasonable to avoid administering this intervention to patients who, given the current evidence, would not appear to derive any benefit from this intervention. Resources and other considerations Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Systemic corticosteroids Comparator: Standard care Summary Evidence summary Please see evidence summary above (placed under recommendation for patients with severe and critical COVID-19 to find more information about the eight RCTs pooled into two systematic reviews with meta-analysis. It also provides information about additional systematic reviews used to inform safety outcomes and results of subgroup analyses resulting in separate recommendations for patients with non-severe COVID-19 and those with severe and critical illness. The GRADE Summary of Findings table shows the relative and absolute effects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with non-severe COVID-19, with certainty ratings. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Relative risk 1.22 (CI 95% 0.93 — 1.61) Based on data from 1535 participants in 1 study. 1 Follow up: 28 days. 23 per 1000 Difference: 28 per 1000 5 more per 1000 ( CI 95% 2 fewer — 14 more ) Low Due to serious risk of bias and serious imprecision 2 Systemic corticosteroids may increase the risk of 28-day mortality in patients with non-severe COVID-19. Need for invasive mechanical ventilation 28 days Relative risk 0.74 (CI 95% 0.59 — 0.93) Based on data from 5481 participants in 2 studies. Follow up: 28 days. 116 per 1000 86 per 1000 Moderate Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need for mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 115 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary ( CI 95% 48 fewer — 8 fewer ) Gastrointestinal bleeding Relative risk 1.06 (CI 95% 0.85 — 1.33) Based on data from 5403 participants in 30 studies. 4 48 per 1000 Difference: 51 per 1000 3 more per 1000 ( CI 95% 7 fewer — 16 more ) Low Due to serious indirectness and serious imprecision 5 Corticosteroids may not increase the risk of gastrointestinal bleeding. Super-infections Relative risk 1.01 (CI 95% 0.9 — 1.13) Based on data from 6027 participants in 32 studies. 186 per 1000 Difference: 188 per 1000 2 more per 1000 ( CI 95% 19 fewer — 24 more ) Low Due to serious indirectness, Due to serious imprecision 6 Corticosteroids may not increase the risk of super-infections. Hyperglycaemia Relative risk 1.16 (CI 95% 1.08 — 1.25) Based on data from 8938 participants in 24 studies. 286 per 1000 Difference: 332 per 1000 46 more per 1000 ( CI 95% 23 more — 72 more ) Moderate Due to serious indirectness 7 Corticosteroids probably increase the risk of hyperglycaemia. Hypernatremia Relative risk 1.64 (CI 95% 1.32 — 2.03) Based on data from 5015 participants in 6 studies. 40 per 1000 Difference: 66 per 1000 26 more per 1000 ( CI 95% 13 more — 41 more ) Moderate Due to serious indirectness 8 Corticosteroids probably increase the risk of hypernatremia. Neuromuscular weakness Relative risk 1.09 (CI 95% 0.86 — 1.39) Based on data from 6358 participants in 8 studies. 69 per 1000 Difference: 75 per 1000 6 more per 1000 ( CI 95% 10 fewer — 27 more ) Low Due to serious indirectness and serious imprecision 9 Corticosteroids may not increase the risk of neuromuscular weakness. Neuropsychiatri c effects Relative risk 0.81 (CI 95% 0.41 — 1.63) Based on data from 1813 participants in 7 studies. 35 per 1000 Difference: 28 per 1000 7 fewer per 1000 ( CI 95% 21 fewer — 22 more ) Low Due to serious indirectness and serious imprecision 10 Corticosteroids may not increase the risk of neuropsychiatric effects. Duration of hospitalization 13 days 12 days Low Due to serious risk of bias and serious imprecision 11 Steroids may result in an important reduction in the duration of hospitalizations. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 116 of 142 Difference: 30 fewer per 1000 Measured by: days Lower better Based on data from 6425 participants in 1 study. (Randomized controlled) 1. Systematic review [1] . Baseline/comparator: Primary study[15]. We derived baseline risk for mortality and mechanical ventilation from the control arm of the WHO SOLIDARITY trial. 2. Risk of bias: serious. lack of blinding. Imprecision: serious. 3. Risk of bias: serious. lack of blinding. 4. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [1], 5. Indirectness: serious. Imprecision: serious. 6. Indirectness: serious. Imprecision: serious. 7. Indirectness: serious. 8. Indirectness: serious. 9. Indirectness: serious. Imprecision: serious. 10. Indirectness: serious. Imprecision: serious. 11. Risk of bias: serious. lack of blinding. Imprecision: serious. confidence interval includes no benefit. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 117 of 142 7. Methods: how this guideline was created This living WHO 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) (161). Related guidelines This living WHO guideline for COVID-19 treatments is related to the larger, more comprehensive guidance for COVID-19 Clinical management: living guideline, which has a wider scope of content and has been regularly updated (6). The first ten versions of this WHO Therapeutics and COVID-19: living guideline, addressing corticosteroids, remdesivir, hydroxychloroquine, lopinavir/ritonavir, ivermectin, IL-6 receptor blockers, casirivimab-imdevimab (neutralizing monoclonal antibodies), convalescent plasma, JAK inhibitors, sotrovimab, molnupiravir, remdesivir and nirmatrelvir-ritonavir can be accessed via the WHO website (4). Guidelines regarding the use of drugs to prevent (rather than treat) COVID-19 are included in a separate document, WHO Living guideline: Drugs to prevent COVID-19, that can be accessed via the WHO website and the BMJ (8). Timing This guideline is living – dynamically updated and globally disseminated once new evidence warrants a change in recommendations (162). The aim is for a six-week timeframe from the public availability of trial data that trigger the guideline development process to WHO publication, while maintaining standards for trustworthy guidelines (WHO Handbook for guideline development) (161)(163). Stepwise approach Here we outline the approach, involving simultaneous processes, taken to improve efficiency and timeliness of development and dissemination of living, trustworthy guidance. Step 1: Evidence monitoring and mapping and triggering of evidence synthesis Comprehensive daily monitoring of all emerging RCTs occurs on a continuous basis, within the context of the living systematic review and network meta-analysis (NMA), using experienced information specialists, who review all relevant information sources for new RCTs addressing interventions for COVID-19. Incorporating pre-print data, which have not yet undergone peer review, promote rapid data sharing in a public health emergency and its inclusion can accelerate the assessment and clinical use of COVID-19 therapeutic interventions. Guidelines are periodically updated to assess data that have undergone peer review in the intervening period and new data. Once practice-changing evidence, or increasing international interest, are identified, the WHO Therapeutics Steering Committee triggers the guideline development process. The trigger for producing or updating specific recommendations is based on the following (any of the three may initiate a recommendation): • likelihood to change practice; • sufficient RCT data on therapeutics to inform the high-quality evidence synthesis living systematic review; • relevance to a global audience. Step 2: Convening the GDG WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise, and patient representatives. For each intervention, the technical unit collected and managed declarations of interests (DOIs) and found no GDG member and co-chairs to have a conflict of interest. In addition to the distribution of a DOI form, during the meeting, the WHO Secretariat described the DOI process and an opportunity was given to GDG members to declare any interests not provided in written form. No verbal conflicts were declared. Web searches did not identify any additional interests that could be perceived to affect an individual’s objectivity and independence during the development of the recommendations. The pre-selected expert GDG (see Section 10) convened on 07 April 2022 to address fluvoxamine and colchicine. The meeting involved a review of the basics of GRADE methodology including formulating population, intervention, comparator, outcome (PICO) questions and subgroups of interests, and prioritization of patient-important outcomes (see step 4 below). The GDG subsequently reviewed analyses, including pre-specified subgroup analyses presented in summary of findings tables, considered an individual patient perspective and feasibility issues specific to this intervention, and formulated recommendations. The GDG also reviewed the mechanism of actions and non-clinical evidence around safety. Step 3: Evidence synthesis The living systematic review/NMA team, as requested by the WHO Therapeutics Steering Committee, performed an independent systematic review to examine the benefits and harms of the interventions (1). The systematic review team includes systematic review experts, clinical experts, clinical epidemiologists and biostatisticians. Team members have expertise in GRADE methodology and rating certainty of evidence specifically in NMAs, including direct and indirect comparisons of treatment alternatives. The NMA team Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 118 of 142 considered deliberations from the initial GDG meeting, specifically focusing on the outcomes and subgroups prioritized by the GDG and produced GRADE evidence summaries to inform development of recommendations. In situations where no head-to-head comparisons of therapeutics were available from RCTs, the LNMA team performed indirect comparisons and produced additional GRADE evidence summaries that the GDG used to inform recommendations. The methods team rated credibility of subgroups using the ICEMAN tool (110). The technical unit collected and managed declarations of interests (DOIs) and found no SR team member to have a conflict of interest. Step 4: Final recommendations The GRADE approach provided the framework for establishing evidence certainty and generating both the direction and strength of recommendations (164)(165). A priori voting rules informed procedures if the GDG failed to reach consensus. There was no need for voting. The following key factors informed transparent and trustworthy recommendations: • absolute benefits and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE summary of findings tables) (166); • quality/certainty of the evidence (164)(167); • values and preferences of patients (168); • resources and other considerations (including considerations of feasibility, applicability, equity) (168); • effect estimates and confidence intervals for each outcome, with an associated rating of certainty in the evidence, as presented in summary of findings tables. If such data are not available, the GDG reviews narrative summaries (166); • recommendations are rated as either conditional or strong, as defined by GRADE. If the GDG members disagree regarding the evidence assessment or strength of recommendations, WHO will apply voting according to established rules (165)(168). When possible, we used research evidence to inform discussion around these key factors. If not available, discussion of these factors was informed by expert opinion, supported by surveys of the GDG members as outlined below. Benefits and harms The GDG members prioritized outcomes (rating from 9 [critical] to 1 [not important] ) in patients with non-severe COVID-19 and in patients with severe and critical COVID-19, taking a patient perspective (Tables 1 and 2 below). The GDG's questions were structured using the PICO format (see evidence profile under the recommendations). The prioritization was performed through a survey, most lately in May 2021, followed by a GDG discussion. These prioritized outcomes were used to update the LNMA (2). Selecting and rating the importance of outcomes GDG members prioritized outcomes from the perspective of patients with non-severe illness (Table 1) and severe and critical illness (Table 2). Table 1. GDG outcome rating from the perspective of patients with non-severe illness Outcome Mean SD Range Admission to hospital 8.5 0.7 7-9 Death 8.1 1.9 3-9 Quality of life 7.5 1.3 5-9 Serious adverse effects (e.g. adverse events leading to drug discontinuation) 7.4 1.8 3-9 Time to symptom resolution 7.3 1.7 4-9 Duration of hospitalization 6.6 0.9 5-8 Duration of oxygen support 6.6 1.2 5-9 Need for invasive mechanical ventilation 5.9 2.3 1-8 New non-SARS-CoV-2 infection 5.6 2.1 3-9 Time to viral clearance 5.5 2.4 1-9 Duration of invasive mechanical ventilation 5.4 2.1 1-8 SD: standard deviation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 119 of 142 Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. Table 2. GDG outcome rating from the perspective of patients with severe and critical illness Outcome Mean SD Range Death 9.0 0 9 Need for invasive mechanical ventilation 8.2 0.9 6-9 Duration of invasive mechanical ventilation 7.6 0.9 6-9 Quality of life 6.9 1.3 5-9 Duration of hospitalization 6.7 1.2 4-9 Serious adverse effects (e.g. adverse events leading to drug discontinuation) 6.7 1.8 3-9 Time to symptom resolution 6.5 1.6 4-9 New non-SARS-CoV-2 infection 6.4 1.8 3-9 Duration of oxygen support 6.3 1.3 4-9 Time to viral clearance 4.7 2.3 1-9 SD: standard deviation. Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. Derivation of absolute effects for drug treatments For patients with non-severe illness, we used the median of the control arm of the RCTs that contributed to the evidence, identified in the LNMA (1)(2) . For admission to hospital, the GDG defined a 10% (100 admissions per 1000 patients) threshold for a baseline risk that would reflect an important absolute benefit for the therapeutics under consideration (i.e., 60 fewer admissions per 1000 patients). For patients with severe and critical illness, the GDG identified the control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, as representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation. Systemic corticosteroids now represent standard of care in patients with severe and critical COVID-19 (see strong recommendation issued by WHO September 2020). Therefore, the baseline risk estimates in the evidence summaries for JAK inhibitors, convalescent plasma and IL-6 receptor blockers were adjusted for treatment effects of corticosteroids for the outcome of mortality and mechanical ventilation. The applied baseline risk estimate for mortality was 13% (130 deaths per 1000 patients). For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence. Specific deliberations on baseline risk are presented for each recommendation. The GDG acknowledged that baseline risks, and thus absolute effects, may vary significantly geographically and over time. Thus, users of this guideline may prefer estimating absolute effects by using local event rates. Values and preferences We had insufficient information to provide the GDG with an evidence-based description of patient experiences or values and preferences regarding treatment decisions for COVID-19 drug treatments. The GDG, therefore, relied on their own judgments of what well-informed patients would value after carefully balancing the benefits, harms, and burdens of treatment. Judgments on values and preferences were crucially informed through the experiences of former COVID-19 patients, represented in the GDG. The GDG agreed that the following values and preferences would be typical of well-informed patients: • Most patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on outcomes they consider important. This was particularly so when evidence suggested treatment effects, if they do exist, are small, and the possibility of important harm remains. • In an alternative situation with larger benefits and less uncertainty regarding both benefits and harms, more patients would be inclined to choose the intervention. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 120 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) acceptability, equity and cost were important considerations. Specific deliberations on values and preferences and associated feasibility and resource related considerations are presented for each recommendation. Step 5: External and internal review An external review group reviewed the final guideline document to identify factual errors, and to comment on clarity of language, contextual issues and implications for implementation. The technical unit collected and managed declarations of interests (DOIs) of the external reviewers and found no external reviewer to have a conflict of interest. However, for certain therapeutics, pharmaceutical company technical representative may be asked to comment on a new drug from the industry perspectives, in line with the WHO Handbook (page 70), as comments from such individuals or organizations on a draft guideline may be helpful in anticipating and dealing with controversy, identifying factual errors, and promoting engagement with all stakeholders. Comments on contextual issues were considered taking into account their interests. The conflict of interest of such individuals will be transparent, as their affiliation will appear in the acknowledgement section. The guideline was then reviewed and approved by the WHO GRC and the Publication Review Committee. 121 of 142 In addition to taking an individual patient perspective, the GDG also considered a population perspective in which feasibility, 8. How to access and use this guideline This is a living guideline from WHO. The recommendations included here will be updated, and new recommendations will be added for other drugs for COVID-19. How to access the guideline: • WHO website in PDF format (4): This is a full read out of the MAGICapp content for those without reliable web access. It can also be downloaded directly from MAGICapp (see cogwheel on top right). • MAGICapp in online, multilayered formats: This is the fullest version of the guideline, as detailed below. • BMJ Rapid Recommendations (5): Designed with clinical readers in mind and including an interactive infographic to summarize all treatments included. • WHO Academy app: Mobile application available for health workers and public on Apple Store and Google Play with a full Case Management section which includes Guidance, Training and Tools, including the latest training modules on Therapeutics for COVID-19. Includes treatment and other guidelines and training materials from WHO on COVID-19 for use offline. • WHO COVID-19 Clinical Care Pathway is a new tool that summarizes these recommendations in a concise and easy to understand manner for health workers. It links this guideline to WHO guidelines on Diagnostic testing for SARS-CoV-2 and Antigen-detection in the diagnosis of SARS-CoV-2 infection to aid in implementation. How to navigate this guideline The guideline is written, disseminated, and updated in MAGICapp, with a format and structure that ensures user-friendliness and ease of navigation (163). It accommodates dynamic updating of evidence and recommendations that can focus on what is new while keeping existing recommendations, as appropriate, within the guideline. The purpose of the online formats and additional tools, such as the infographics, is to make it easier to navigate and make use of the guideline in busy clinical practice. The online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting evidence and other information pertinent to applying the recommendations in practice, including tools for shared decision-making (clinical encounter decision aids) (163). Fig. 4 shows how the online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting information pertinent to applying the recommendations in practice. End-users will also need to understand what is meant by strong and conditional recommendations (displayed immediately below) and certainty of evidence (the extent to which the estimates of effect from research represent true effects from treatment). For each recommendation additional information is available through the following tabs: • Research evidence: Readers can find details about the research evidence underpinning the recommendations as GRADE Summary of Findings tables and narrative evidence summaries (shown in Fig. 4). • Evidence to decision: The absolute benefits and harms are summarized, along with other factors such as the values and preferences of patients, practical issues around delivering the treatment as well as considerations concerning resources, applicability, feasibility, equity and human rights. These latter factors are particularly important for those in need of adapting the guidelines for the national or local context. • Justification: Explanation of how the GDG considered and integrated evidence to decision factors when creating the recommendations, focussing on controversial and challenging issues. • Practical information: For example, dosing, duration and administration of drugs, or how to apply tests to identify patients in practice. • Decision aids: Tools for shared decision-making in clinical encounters. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 122 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 123 of 142 Fig. 4. Example of how research evidence is available one click away, with narrative evidence summary giving additional details to GRADE Summary of Findings table This living guideline from WHO is also used to inform the activities of the WHO Prequalification of Medicinal Products. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 124 of 142 Additional educational modules and implementation tools for health workers: • WHO COVID-19 essential supplies forecasting tool (COVID-ESFT) assists governments, partners, and other stakeholders to forecast the necessary volume of personal protective equipment, diagnostic test equipment, consumable medical supplies, biomedical equipment for case management, and essential drugs for supportive care and treatment of COVID-19. • WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation provides algorithms and practical tools for clinicians working in acute care hospitals managing adult and paediatric patients with acute respiratory infection, including severe pneumonia, acute respiratory distress syndrome, sepsis and septic shock. This includes information on screening, testing, monitoring and treatments. • WHO Openwho.org clinical management course series hosts a full course series on COVID-19 which covers a holistic pathway of care for a patient, from screening and triage to rehabilitation, testing and treatments and palliative care. • Safety monitoring of molnupiravir for treatment of mild to moderate COVID-19 infection in low and middle-income countries using cohort event monitoring: a WHO study. 9. Uncertainties, emerging evidence and future research The guideline recommendations for COVID-19 therapeutics demonstrate remaining uncertainties concerning treatment effects for all outcomes of importance to patients. There is also a need for better evidence on prognosis and on values and preferences of patients with COVID-19. Here we outline key uncertainties for fluvoxamine and colchicine identified by the GDG, adding to those for remdesivir, nirmatrelvir- ritonavir, molnupiravir, JAK inhibitors, sotrovimab, convalescent plasma casirivimab-imdevimab, ivermectin, corticosteroids, remdesivir, hydroxychloroquine, lopinavir-ritonavir, and IL-6 receptor blockers identified when recommendations were initially formulated in previous versions of the living guideline. These uncertainties may inform future research, i.e. the production of higher certainty and more relevant evidence to inform policy and practice. We also outline emerging evidence in the rapidly changing landscape of trials for COVID-19. Ongoing uncertainties and opportunities for future research Fluvoxamine The panel's recommendation reflects the panel's perception that the current evidence does not justify using fluvoxamine to treat COVID-19. However, the panel has not implied that fluvoxamine was proven to be ineffective. Decisions to further investigate the effects of fluvoxamine for COVID-19 will likely hinge on how stakeholders perceive the opportunity cost of investigating the effects of fluvoxamine over other candidate therapies. The panel discussions illuminated the following knowledge gaps: • What are the effects of fluvoxamine in patients who suffer from a combination of non-severe COVID-19 at risk of deteriorating and significant symptoms of anxiety? • What are the side-effects of fluvoxamine therapy in patients with non-severe COVID-19 at risk of deteriorating? • What proportion of patients with non-severe COVID-19 at risk of deteriorating would be ineligible due to risk of pharmacological interactions? The panel surmised that, in the future, investigators would have to carefully consider whether fluvoxamine could still be compared with placebo or no treatment given that effective treatments are available. If the rationale to further investigate fluvoxamine is its advantageous cost and availability, non-inferiority designs may be considered. Colchicine The GDG panel believed that it was unlikely future studies would identify subgroups of patients who may benefit from colchicine. Remdesivir and nirmatrvelvir-ritonavir • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • resistance and efficacy against newer variants of interest; • efficacy in immunocompromised, vaccinated, children, pregnant patients, and other specific subgroups of patients • optimal duration of therapy • combination therapy with other COVID-19 drugs, and head-to-head comparison against other antiviral agents Molnupiravir • need for clinical data to investigate safety and applicability concerns (including in children, lactating or pregnant women, and men; and long-term impact on mutagenesis and cancer risk); • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • data to inform individual and population-level concerns, such as the emergence of resistance and efficacy against new variants; • comparative effectiveness of molnupiravir compared with other treatment options (eg. monoclonal antibodies or other antivirals) in the non-severe population, including combination therapy; • the relative intracellular nucleotide ratios of endogenous: molnupiravir cell lines and animal models to assess genetic toxicity; • how readily mutations arise under a selective pressure with NHC in vitro and molnupiravir in animal models and patients with SARS- CoV-2 infection; • if mutations arising under selective pressure in vitro, in vivo or in humans: ◦ confer a decreased antiviral activity for NHC; ◦ arise in the spike protein and/or do they confer an increase in replicative potential/transmission. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 125 of 142 JAK inhibitors • incremental benefit for patients receiving baricitinib and IL-6 receptor blockers together, rather than either drug individually; • relative benefits of tofacitinib and ruxolitinib to baricitinib; • safety and efficacy in children, and pregnant and lactating women. Sotrovimab • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19, in order to best identify patients who would most benefit from this intervention; • efficacy and safety for severe and critical seronegative COVID-19 patients, for patients infected with emerging variants, as well as in children and pregnant women. Convalescent plasma • effects in severe and critical illness (low to moderate certainty evidence for most patient-important outcomes); • long-term mortality and functional outcomes in COVID-19 survivors; • safety and efficacy in children, pregnant, and lactating women; • effects of high-titre convalescent plasma on mortality and other patient-important outcomes; • effects in patients with seronegative antibody status. Casirivimab-imdevimab • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • dosing and administration routes in non-severe and severe/critical COVID-19 patients; • safety and efficacy in children and pregnant women. IL-6 receptor blockers • long-term mortality and functional outcomes in COVID-19 survivors; • safety data in terms of nosocomial infections; • data in children, pregnant patients and those that are already immunocompromised; • patients with non-severe COVID-19; • immunity and the risk of a subsequent infection, which may impact the risk of death after 28 days; • outcomes by different IL-6 receptor blocker dosing and optimal timing of drug initiation. Ivermectin Given the very low certainty in estimates for most critical outcomes of interest, the GDG felt that further high-quality clinical trials examining this drug would be essential before any recommendation for use as part of clinical care. This includes further RCTs examining both inpatients and outpatients and those with varying disease severities and using different ivermectin dosing regimens. The focus of these studies should be on outcomes important to patients such as mortality, quality of life, need for hospitalization, need for invasive mechanical ventilation and time to clinical or symptom improvement. Also, a better characterization of potential harms with ivermectin in patients with COVID-19 would be important. Hydroxychloroquine Although some uncertainty remains, the GDG panel felt that further research was unlikely to uncover a subgroup of patients that would benefit from hydroxychloroquine on the most important outcomes (mortality, mechanical ventilation) given the consistent results in trials across disease severity and location. Lopinavir-ritonavir Although some uncertainty remains, the GDG panel felt that further research was unlikely to uncover a subgroup of patients that would benefit from lopinavir-ritonavir on the most important outcomes (mortality, mechanical ventilation) given the consistent results in trials across disease severity and location. Corticosteroids • long-term mortality and functional outcomes in COVID-19 survivors; Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 126 of 142 • patients with non-severe COVID-19 (i.e. pneumonia without hypoxaemia); • outcomes, when used in combination with additional therapies for COVID-19, such as novel immunomodulators. It will become increasingly important to ascertain how these interact with systemic corticosteroids. All investigational therapies for severe and critical COVID-19 (including remdesivir) should be compared with systemic corticosteroids or evaluated in combination with systemic corticosteroids vs systemic corticosteroids alone; • immunity and the risk of a subsequent infection, which may impact the risk of death after 28 days; • outcomes, by different steroid preparation, dosing, and optimal timing of drug initiation. Emerging evidence The unprecedented volume of planned and ongoing studies for COVID-19 interventions – over 5000 RCTs as of May 2022 – implies that more reliable and relevant evidence will emerge to inform policy and practice (13) (see appendix). 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 registrations (13), the WHO website and other repositories, such as the COVID-NMA initiative. Whereas most of these studies are small and of variable methodological quality, a number of large, international platform trials (e.g. RECOVERY, SOLIDARITY, and DISCOVERY) are better equipped to provide robust evidence for a number of potential treatment options (14)(15)(16)(17). Such trials can also adapt their design, recruitment strategies, and selection of interventions based on new insights, exemplified by the uncertainties outlined above. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 127 of 142 10. Authorship, contributions, acknowledgements Authorship, contributions, acknowledgements WHO would like to thank the collaborative efforts of all those involved to make this process rapid, efficient, trustworthy and transparent. WHO Therapeutics Steering Committee (updated for fluvoxamine and colchicine) The committee includes representatives from various WHO departments at headquarters and the regions and has been approved by the WHO Director of the Country Readiness Department, and the WHO Chief Scientist. The WHO Secretariat meets on a regular basis to discuss when to trigger guideline updates based on evidence updates from the WHO rapid review team, and other sources of evidence and selects the members of the Guideline Development Group (GDG) for the living guideline. Janet V Diaz (Lead, Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); John Appiah (Lead, Case Management, WHO Regional Office for Africa); Lisa Askie (Quality Assurance of Norms and Standards Department); Silvia Bertagnolio (Communicable and Noncommunicable Diseases Division/Clinical Team for COVID-19 Response); Chiori Kodama (WHO Regional Office for the Eastern Mediterranean); Krutika Kuppalli (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Marta Lado Castro-Rial (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Lorenzo Moja (Health Products Policy and Standards Department); Olufemi Oladapo (Sexual and Reproductive Health and Research Department); Dina Pfeifer (WHO Regional Office for Europe/Health Emergencies Programme); J Pryanka Relan (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Ludovic Reveiz (Evidence and Intelligence for Action in Health Department, Incident Management Systems for COVID-19, Pan American Health Organization); Vaseeharan Sathiyamoorthy (Research for Health, Science Division); Anthony Solomon (Neglected Tropical Diseases); Pushpa Wijesinghe (Lead, Case Management, Regional Office for South-East Asia). Supporting project officers: Julie Viry and Anne Colin (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva). The WHO Therapeutics Steering Committee is fully responsible for decisions about guidance production and convening the GDG. Special thanks to the WHO Pharmacovigilance team for their support and contributions to this update: Noha Iessa and Shanti Pal. Guideline Development Group (GDG) for the update on fluvoxamine recommendation. For list of GDG members of previous recommendations, see here. Diptesh Aryal (Mediciti Hospital, Nepal); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); David Hui (Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong SAR, China); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Marc Mendelson (Division of Infectious Diseases & HIV Medicine at Groote Schuur Hospital, University of Cape Town, UTC); Giovanni Battista Migliori (Pulmonology, Istituti Clinici Scientifii Maygeri IRCCS); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Andre Ricardo Araujo Da Silva (Departamento de Materno Infantil, Universidade Federal Fluminense, Brazil); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for the update on colchicine recommendation. For list of GDG members of previous recommendations, see here. Diptesh Aryal (Mediciti Hospital, Nepal); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); David Hui (Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong SAR, China); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 128 of 142 Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Marc Mendelson (Division of Infectious Diseases & HIV Medicine at Groote Schuur Hospital, University of Cape Town, UTC); Giovanni Battista Migliori (Pulmonology, Istituti Clinici Scientifii Maygeri IRCCS); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Andre Ricardo Araujo Da Silva (Departamento de Materno Infantil, Universidade Federal Fluminense, Brazil); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for the update on remdesivir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Manai Hela (Emergency Medical Service Tunis, Tunisia); Frederique Jacquerioz Bausch (Department of Primary Care, University Hospital of Geneva, Switzerland); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for nirmatrelvir-ritonavir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Stephen Freedman (Department of Pediatrics, Cumming School of Medicine, University of Calgary, Canada); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Arthur Kwizera (Makerere University College of Health Sciences, Mulago National Referral Hospital ICU, Uganda); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for molnupiravir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Patrick Gee (patient panel member, Virginia, United States); Matthias Gotte (University of Alberta, Canada); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); Beverley Hunt (King's College London, United Kingdom); Frederique Jacquerioz Bausch (Department of Primary Care, University Hospital of Geneva, Switzerland); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Fyezah Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 129 of 142 Jehan (Aga Khan University, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Arthur Kwizera (Makerere University College of Health Sciences, Mulago National Referral Hospital ICU, Uganda); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Imelda Mahaka (Pangaea Zimbabwe AIDS Trust, Harare, Zimbabwe); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom); Ananda Wijewickrama (Ministry of Health, Sri Lanka). Guideline Development Group (GDG) for JAK inhibitors recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Carolyn S Calfee (University of California, San Francisco); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Beverley Hunt (King's College London, United Kingdom); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Sanjeev Krishna (St George’s University of London, United Kingdom); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College London, United Kingdom); Ananda Wijewickrama (Ministry of Health, Sri Lanka); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore). Guideline Development Group (GDG) for sotrovimab recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Beverley Hunt (King's College, London); Fyezah Jehan (Aga Khan University, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom), Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Ronald Swanstrom (University of North Carolina, United States); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore). Guideline Development Group (GDG) for convalescent plasma guideline. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Patrick Gee (patient panel member, United States of America); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Madiha Hashmi (Ziauddin University, Karachi, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Leticia Kawano-Dourado (Research Institute, Hospital do Coração, São Paulo, Brazil); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Greta Mino (Alcivar Hospital in Guayaquil, Ecuador); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College, London); Ananda Wijewickrama (Ministry of Health, Sri Lanka). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 130 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) Methods chairs Gordon Guyatt (casirivimab-imdevimab, JAK inhibitors, nirmatrelvir-ritonavir), Bram Rochwerg (IL-6 receptor blockers, ivermectin, remdesivir and lopinavir-ritonavir, convalescent plasma, molnupiravir, remdesivir update), Reed Siemieniuk (hydroxychloroquine), Francois Lamontagne (corticosteroids, sotrovimab, colchicine, fluvoxamine, fluvoxamine, colchicine). Clinical chairs Michael Jacobs (casirivimab-imdevimab, IL-6 receptor blockers, ivermectin, remdesivir, hydroxychloroquine, lopinavir-ritonavir, JAK inhibitors, remdesivir update), Yee-Sin Leo (corticosteroids), Leticia Kawano-Dourado (convalescent plasma, sotrovimab, molnupiravir), Miriam Stegemann (fluvoxamine, colchicine). Methods resource persons Arnav Agarwal (University of Toronto, Canada); Thomas Agoritsas (University Hospitals of Geneva, Switzerland); Romina Brignardello- Petersen (McMaster University, Canada); Gordon H Guyatt (McMaster University, Canada); George Tomlinson (Department of Medicine, University Health Network, Toronto, Canada); Per Olav Vandvik (MAGIC, University of Oslo Norway); Linan Zeng (West China Second University Hospital, Sichuan University, Chengdu, China; McMaster University, Canada). Guideline Support Collaboration Committee which provides the coordination between WHO and MAGIC to allow the rapid development of the WHO guideline and its dissemination into the various publication platforms: Thomas Agoritsas (MAGIC, University Hospitals of Geneva); Janet Diaz (World Health Organization); Helen Macdonald (British Medical Journal); Gordon Guyatt (McMaster University, Canada); Per Olav Vandvik (MAGIC, University of Oslo); Julie Viry (World Health Organization). Temporary advisors: Special thanks to Professor Andrew Owen (Department of Molecular and Clinical Pharmacology, University of Liverpool) for his contributions in the pharmacokinetics of ivermectin, IL-6 receptor blockers, casirivimab-imdevimab, convalescent plasma and the monoclonal antibodies, JAK inhibitors, sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir update, fluvoxamine, colchicine). Special thanks to Professor Craig Thompson (University of Oxford) for his contributions in diagnostic testing as it relates to the casrivimab-imdevimab guideline. External reviewers Special thanks to the external reviewers for their insights on convalescent plasma, casrivimab-imdevimab, IL-6 receptor blockers, ivermectin, sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir, fluvoxamine and colchicine. Aula Abbara (Médecins Sans Frontières); Yaseen Arabi (King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia); Marcio da Fonseca (Médecins Sans Frontières); Richard Kojan (Alliance for International Medical Action); Carolina Nanclares (Médecins Sans Frontières); Saschveen Singh (Médecins Sans Frontières). Special thanks to Paula Dakin (Regeneron Pharmaceuticals Inc) who was invited to comment on on casirimab-imdevimab (version six) to identify factual errors, and to comment on clarity of language, contextual issues and implications for implementation. Their comments were considered taking into account the interests of Regeneron Pharmaceuticals Inc. Special thanks to Lisa Burry (Department of Pharmacy, Mont Sinai Hospital, Toronto) for her contributions to the Practical information sheets as clinical pharmacists (sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir updates). Special thanks to Christine Tsang (Oxford University Hospitals NHS Foundation Trust, UK) for her contributions to the Practical information sheets as clinical pharmacists (molnupiravir, nirmatrelvir-ritonavir, remdesivir updates). Observer Sade Ogunsala (colchicine and fluvoxamine). Infographic Special thanks to the BMJ for providing the infographic for this guideline. Funding Many thanks to the Bill & Melinda Gates Foundation, Norwegian Directorate of Public Health and Germany. Special thanks to the MAGIC Evidence Ecosystem Foundation, which provides pro bono methodologic support. 131 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) Meta-analysis teams Special thanks to the McMaster University LNMA team Arnav Agarwal (University of Toronto, Canada); Thomas Agoritsas (MAGIC; University Hospitals of Geneva, Switzerland); Jessica J Bartoszko (McMaster University, Canada); Romina Brignardello-Petersen (McMaster University, Canada); Derek K Chu (McMaster University, Canada); Rachel Couban (McMaster University, Canada); Andrea Darzi (McMaster University, Canada); Tahira Devji (McMaster University, Canada); Bo Fang (Chongqing Medical University, China); Carmen Fang (William Osler Health Network, Canada); Signe Agnes Flottorp (University of Oslo, Norway); Farid Foroutan (McMaster University, Canada); Long Ge (Lanzhou University, China); Gordon H Guyatt (McMaster University, Canada); Mi Ah Han (Chosun University, Republic of Korea); Diane Heels-Ansdell (McMaster University, Canada); Kimia Honarmand (Western University, Canada); Liangying Hou (Lanzhou University, China); Xiaorong Hou (Chongqing Medical University, China); Quazi Ibrahim (McMaster University, Canada); Ariel Izcovich (Servicio de Clinica Médica del Hospital Alemán, Argentina); Elena Kum (McMaster University, Canada); Francois Lamontagne (Université de Sherbrooke, Canada); Qin Liu (Chongqing Medical University, China); Mark Loeb (McMaster University, Canada); Maura Marcucci (McMaster University, Canada); Shelley L McLeod (Sinai Health, Canada); Sharhzad Motaghi, (McMaster University, Canada); Srinivas Murthy (University of British Columbia, Canada); Reem A Mustafa (McMaster University, Canada); John D Neary (McMaster University, Canada); Hector Pardo- Hernandez (Sant Pau Biomedical Research Institute, Spain); Anila Qasim (McMaster University, Canada); Gabriel Rada (Epistemonikos Foundation, Chile); Irbaz Bin Riaz (Mayo Clinic Rochester, United States of America); Bram Rochwerg (McMaster University, Canada); Behnam Sadeghirad (McMaster University, Canada); Nigar Sekercioglu (McMaster University, Canada); Lulu Sheng (Chongqing Medical University, China); Reed AC Siemieniuk (McMaster University, Canada); Ashwini Sreekanta (McMaster University, Canada); Charlotte Switzer (McMaster University, Canada); Britta Tendal (Monash University, Australia); Lehana Thabane (McMaster University, Canada); George Tomlinson (University of Toronto, Canada); Tari Turner (Monash University, Australia); Per Olav Vandvik (MAGIC; University of Oslo, Norway); Robin WM Vernooij (University Medical Center Utrecht, Netherlands); Andrés Viteri-García (Epistemonikos Foundation, Chile); Ying Wang (McMaster University, Canada); Liang Yao (McMaster University, Canada); Zhikang Ye (McMaster University, Canada); Dena Zeraatkar (McMaster University, Canada) (1)(2)(3). Special thanks to WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group for their publication: Association of administration of interleukin-6 antagonists with mortality and other outcomes among hospitalized patients with COVID-19: a prospective meta-analysis (116). Manu Shankar-Hari; Claire L Vale; Peter J Godolphin; David Fisher; Julian PT Higgins; Francesca Spiga; Jelena Savović; Jayne Tierney; Nor Arisah Misnan; Gabriel Baron; Julie S Benbenishty; Lindsay R Berry; Niklas Broman; Alexandre Biasi Cavalcanti; Roos Colman; Stefanie L De Buyser; Lennie PG Derde; Pere Domingo; Sharifah Faridah Syed Omar; Ana Fernandez-Cruz; Thijs Feuth; Felipe Garcia; Rosario Garcia-Vicuna; Isidoro Gonzalez-Alvaro; Anthony C Gordon; Richard Haynes; Olivier Hermine; Peter W Horby; Nora K Horick; Kuldeep Kumar: Bart N Lambrecht; Martin J Landray; Lorna Leal; David J Lederer; Elizabeth Lorenzi; Xavier Mariette; Nicolas Merchante; Nor Arisah Misnan; Shalini V Mohan; Michael C Nivens; Jarmo Oksi; Jose A Perez-Molina; Reuven Pizov; Raphael Porcher; Simone Postma; Reena Rajasuriar; Athimalaipet V Ramanan; Pankti D Reid; Abraham Rutgers; Aranzazu Sancho-Lopez; Todd B Seto; Sumathi Sivapalasingam; Arvinder Singh Soin; Natalie Staplin; John H Stone; Garth W Strohbehn; Jonas Sunden-Cullberg; Julian Torre- Cisneros; Larry W Tsai; Hubert van Hoogstraten; Tom van Meerten; Viviane Cordeiro Veiga; Peter Westerwheel; Srinivas Murthy; Janet V Diaz; John C Marshall; Jonathan A C Sterne. 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Therapeutics and COVID-19 LIVING GUIDELINE 14 JULY 2022 {mf~~\ World Health ~•t! Organization guideline © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). 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Otherwise, this interim guidance document will expire 2 years after the date of publication. Sections 1. Summary of the guideline .................................................................................................................................................................................................... 5 2. Abbreviations .......................................................................................................................................................................................................................... 7 3. Introduction ............................................................................................................................................................................................................................ 8 4. What triggered this update and what is coming next? .................................................................................................................................................. 9 5. Understanding and applying the WHO severity definitions ......................................................................................................................................10 6. Recommendations for therapeutics .................................................................................................................................................................................11 6.1 Overview of drugs, recommendations and key issues to consider when applying them .........................................................................11 6.2 Fluvoxamine (published 14 July 2022) .................................................................................................................................................................13 6.2.1 Mechanism of action ...................................................................................................................................................................................19 6.3 Colchicine (published 14 July 2022) .....................................................................................................................................................................20 6.3.1 Mechanism of action ...................................................................................................................................................................................23 6.4 Nirmatrelvir-ritonavir (published 22 April 2022) ...............................................................................................................................................23 6.4.1. Mechanism of action ..................................................................................................................................................................................35 6.5 Remdesivir (published 22 April 2022) ..................................................................................................................................................................36 6.5.1 Mechanism of action ...................................................................................................................................................................................43 6.6 Molnupiravir (published 3 March 2022) ..............................................................................................................................................................43 6.6.1 Mechanism of action ...................................................................................................................................................................................49 6.7 Janus kinase inhibitors (published 14 January 2022) .......................................................................................................................................50 6.7.1 Mechanism of action ...................................................................................................................................................................................61 6.8 Sotrovimab (published 14 January 2022) ............................................................................................................................................................62 6.8.1 Mechanism of action ...................................................................................................................................................................................68 6.9 Convalescent plasma (published 7 December 2021) ........................................................................................................................................68 6.9.1 Mechanism of action ...................................................................................................................................................................................75 6.10 Casirivimab-imdevimab (neutralizing monoclonal antibodies) (published 24 September 2021) ........................................................76 6.10.1 Mechanism of action .................................................................................................................................................................................86 6.11 Interleukin-6 receptor blockers (published 6 July 2021) ...............................................................................................................................87 6.11.1 Mechanism of action .................................................................................................................................................................................93 6.12 Ivermectin (published 31 March 2021) .............................................................................................................................................................94 6.12.1 Mechanism of action .................................................................................................................................................................................99 6.13 Hydroxychloroquine (published 17 December 2020) ....................................................................................................................................99 6.14 Lopinavir-ritonavir (published 17 December 2020) .................................................................................................................................... 104 6.15 Systemic corticosteroids (published 2 September 2020) ........................................................................................................................... 108 7. Methods: how this guideline was created ................................................................................................................................................................... 118 8. How to access and use this guideline ........................................................................................................................................................................... 122 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 3 of 142 9. Uncertainties, emerging evidence and future research ............................................................................................................................................ 125 10. Authorship, contributions, acknowledgements ....................................................................................................................................................... 128 References ............................................................................................................................................................................................................................... 133 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 4 of 142 1. Summary of the 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 randomized controlled trials (RCTs) recently completed and underway. This update adds new recommendations on fluvoxamine and colchicine in patients with non-severe COVID-19; the former was informed by a systematic review of three RCTs with 2196 patients, and the latter by 13 RCTs with 18 172 patients. New recommendations: The Guideline Development Group (GDG) recommends not to use fluvoxamine in patients with non-severe illness, except in the context of a clinical trial. A strong recommendation was made against administering colchicine in patients with non-severe illness. No recommendation was made in patients with severe or critical illness as there are limited or no data on either drug for this population. Several treatment alternatives are now available for patients with non-severe COVID-19 at highest risk of hospitalization. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis (LNMA) have been used (see Section 7 for Methods) to inform 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), co-administered medications, duration of treatment, and time from onset of symptoms to starting treatment in the trials. 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. When recommending against the use of fluvoxamine for patients with non-severe illness except in the context of a clinical trial, the GDG recognized the lack of a clear mechanism of action supporting its efficacy, and low to moderate certainty evidence suggesting little or no effect on hospitalization, mechanical ventilation, and mortality. The panel also noted the absence of reliable data on related serious adverse events, known significant pharmacological interactions, and the large proportion of drug discontinuations in included studies. The panel did not anticipate important variability in patient values and preferences regarding using fluvoxamine, and therefore recommended not to use the drug except in the context of a clinical trial. When recommending against the use of colchicine for patients with non-severe illness, the GDG underscored the evidence showing little or no effect on hospitalization, mechanical ventilation, and mortality (moderate certainty). The GDG also discussed the known risks of drug interactions, and colchicine's narrow therapeutic window, particularly in patients with or at risk of hepatic and renal failure. Colchicine toxicity can be severe, and sometimes fatal. Prior recommendations: Recommended for patients with severe or critical COVID-19: • a strong recommendation for systemic corticosteroids; • a strong recommendation for interleukin-6 (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; • a conditional recommendation for casirivimab-imdevimab for patients with seronegative status, where rapid viral genotyping is available and confirms infection with a susceptible SARS-CoV-2 variant. Recommended for patients with non-severe COVID-19 at highest risk of hospitalization: • a strong recommendation for nirmatrelvir-ritonavir; • a conditional recommendation for molnupiravir; • a conditional recommendation for sotrovimab; • a conditional recommendation for casirivimab-imdevimab, where rapid viral genotyping is available and confirms infection with a susceptible SARS-CoV-2 variant; • a conditional recommendation for remdesivir. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 5 of 142 Not recommended for patients with non-severe COVID-19: • a conditional recommendation against systemic corticosteroids; • a strong recommendation against convalescent plasma. Not recommended for patients with non-severe COVID-19 at low risk of hospitalization: • a conditional recommendation against nirmatrelvir-ritonavir. Not recommended for patients with severe and critical COVID-19: • a recommendation against convalescent plasma, except in the context of a clinical trial; • 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; • 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 fluvoxamine and colchicine for patients with non-severe COVID-19. The GDG typically evaluates a drug 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. It is supported by LNMAs (1)(2)(3). Updates and access: This is the eleventh version (tenth update) of the living guideline. It replaces earlier versions (2 September 2020, 20 November 2020, 17 December 2020, 31 March 2021, 6 July 2021, 24 September 2021, 7 December 2021, 14 January 2022, 3 March 2022 and 22 April 2022). The current guideline and its earlier versions are available through the WHO website (4), the BMJ (5), and MAGICapp (online and also as PDF outputs for readers with limited internet access). The living guideline is written, disseminated, and updated in an online platform (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 updated within the guideline. This living WHO guideline for COVID-19 treatments is related to the larger, more comprehensive guideline for COVID-19 clinical management (6). Guidelines for the use of drugs to prevent (rather than treat) COVID-19 are published separately on the WHO website (7) and by the BMJ (8), supported by a LNMA (9). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 6 of 142 2. Abbreviations ALT alanine aminotransferase ARDS acute respiratory distress syndrome CAP community-acquired pneumonia CI confidence interval COVID-19 coronavirus disease 2019 DOI declaration of interests eGFR estimated glomerular filtration rate FDA United States Food and Drug Administration GDG Guideline Development Group GI gastrointestinal GRADE Grading of Recommendations Assessment, Development and Evaluation GRC guideline review committee IL-6 interleukin-6 IMV invasive mechanical ventilation JAK Janus kinase LNMA living network meta-analysis LMIC low- and middle-income countries MAGIC Magic Evidence Ecosystem Foundation MD mean difference OIS optimal information size OR odds ratio PICO population, intervention, comparator, outcome PMA prospective meta-analysis RCT randomized controlled trial RR relative risk/risk ratio SAE serious adverse event SSRI selective serotonin reuptake inhibitor TACO transfusion-associated circulatory overload TRALI transfusion-related acute lung injury WHO World Health Organization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 7 of 142 3. Introduction Info Box As of May 2022, there have been over 524 million confirmed cases of COVID-19 (10). The pandemic has thus far claimed approximately 6.2 million lives (10). Vaccination is having a substantial impact on hospitalizations and death in a number of high- income countries, but limitations in global access to vaccines mean that many populations remain vulnerable (10)(11). Even in vaccinated individuals, uncertainties remain about the duration of protection and effectiveness of current vaccines – and the efficacy of existing treatments for COVID-19 – against emerging SARS-CoV-2 variants. Taken together, there remains a need for more effective treatments for COVID-19. The COVID-19 pandemic – and the explosion of both research and misinformation – has highlighted the need for trustworthy, accessible, and regularly updated living guidance to place emerging findings into context and provide clear recommendations for clinical practice (12). This living guideline responds to emerging evidence from RCTs on existing and new drug treatments for COVID-19. More than 5000 trials investigating interventions for COVID-19 have been registered and are ongoing or completed (see Section 9 for emerging evidence and linked appendix) (13). Among these are large national and international platform trials (such as ACCT, RECOVERY, WHO SOLIDARITY, REMAP-CAP, and ACTIV), which recruit large numbers of patients in many countries, with a pragmatic and adaptive design (14)(15)(16)(17). An overview of ongoing trials is available from the Infectious Diseases Data Observatory, through their living systematic review of COVID-19 clinical trial registrations (13) and the WHO website. Several LNMAs associated with this guideline incorporate emerging trial data and allow for analysis of comparative effectiveness of multiple COVID-19 treatments. To inform the living guidance, we also use additional relevant evidence on safety, prognosis, and patient values and preferences related to COVID-19 treatments. A recently updated living systematic review of 232 risk prediction models in hospitalized patients with COVID-19 identified two promising risk prediction tools that could inform recommendations in this eleventh version of the guideline; these include the Jehi diagnostic model and the 4C mortality model (see Section 6.1 for more details) (18). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 8 of 142 4. What triggered this update and what is coming next? This eleventh version of the WHO living guideline addresses the use of fluvoxamine and colchicine in non-severe COVID-19. It follows the availability of three and seven RCTs, respectively, which were incorporated in an update to the LNMA on drug treatments for COVID-19 (1) . Fig. 1 shows other therapeutics in progress for this WHO living guideline, also communicated through the WHO portal (4). Each dot represents a week of time. In deciding which therapeutics to cover, the WHO considers multiple factors, including the extent of available evidence to inform recommendations, and makes a judgment on whether and when additional evidence might be anticipated. The WHO has a standing Steering Committee (see Section 10) to evaluate possibilities for new drug recommendations and updates to existing drug recommendations. Fig. 1. COVID-19 therapeutics under assessment Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 9 of 142 5. Understanding and applying the WHO severity definitions Info Box This guideline applies to all patients with COVID-19. Recommendations may differ based on the severity of COVID-19, according to WHO severity definitions (see below) (6). These definitions avoid reliance on access to health care to define patient subgroups. WHO definitions of disease severity for COVID-19 • Critical COVID-19 – Defined by the criteria for acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation (invasive or non-invasive) or vasopressor therapy. • Severe COVID-19 – Defined by any of: ◦ oxygen saturation < 90% on room air; ◦ signs of pneumonia; ◦ signs of severe respiratory distress (in adults, accessory muscle use, inability to complete full sentences, respiratory rate > 30 breaths per minute; and, in children, very severe chest wall in-drawing, grunting, central cyanosis, or presence of any other general danger signs including inability to breastfeed or drink, lethargy, convulsions or reduced level of consciousness). • Non-severe COVID-19 – Defined as the absence of any criteria for severe or critical COVID-19. Caution: The GDG noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary, and should be interpreted cautiously when defining disease severity. For example, clinicians must use their judgment to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient with chronic lung disease. Similarly, clinicians may interpret a saturation of 90–94% on room air as abnormal in the patient with normal lungs, and as an early sign of severe disease in patients with a downward clinical trajectory. Generally, in cases wherethere is doubt, the GDG suggested erring on the side of considering disease as severe. The infographic illustrates these three disease severity groups and key characteristics to apply in practice. Infographic co-produced by the BMJ and MAGIC; designer Will Stahl-Timmins (see BMJ Rapid Recommendations). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 10 of 142 6. Recommendations for therapeutics Considerations for decision-making 6.1 Overview of drugs, recommendations and key issues to consider when applying them Info Box The infographic summarizes WHO recommendations, mapped against the WHO severity criteria. When applying the recommendations, clinicians should also consider the following key issues: How to choose between therapeutics Several treatment alternatives are available for patients with non-severe COVID-19, and for those with severe or critical COVID-19. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir and the monoclonal antibodies), co-administered medication, duration of treatment, and time from onset of symptoms to starting treatment in the trials. Some can be used in combination (i.e. as for severe or critical COVID-19) while others are to be used as alternatives. Recommended combinations of treatments are based on direct comparisons from trials demonstrating additional benefit, such as adding baricitinib or interleukin-6 receptor blockers to systemic corticosteroids in patients with severe or critical COVID-19. In the absence of direct comparisons of the various therapeutics in trials, indirect comparisons from the LNMA have been used (see Section 7 - Methods) to inform use of one drug over another with a related mechanism of action. To display the benefits and harms for the alternative therapeutics we provide an interactive decision support tool that can also be used in shared decision-making. Efficacy may vary in the function of specific SARS-CoV-2 variants. For example, previously recommended antibodies may be less effective for the Omicron BA.1/BA.2 variant. How to identify patients with non-severe COVID-19 at highest risk of hospitalization. Several recommendations for drugs are only for those at highest risk for hospitalization because the benefit would be trivial (in absolute terms) if everyone with non-severe COVID-19 were to receive treatment; instead, some treatments should be reserved for those at highest risk of hospitalization and given early in the disease course. The panel identified a risk beyond 10% of being hospitalized for COVID-19 to represent a threshold at which most patients with non-severe illness would want to be treated (see Section 7). Reliably identifying those at highest risk is challenging because of the changing global context with evolution of the virus and patterns of vaccination, thus raising importance of validation of models to local context. A living systematic review of 232 risk prediction models for COVID-19 identified two promising risk prediction tools (18) before Omicron circulation. These tools concur that typical characteristics of people at highest risk include those with older age, immunosuppression and/or chronic diseases, with lack of vaccination as an additional risk factor to consider. Updated Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 11 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 12 of 142 6.2 Fluvoxamine (published 14 July 2022) For patients with non-severe COVID-19 Practical Info The GDG made a recommendation against using fluvoxamine for treatment of patients with COVID-19 outside the setting of a clinical trial and therefore practical considerations are less relevant for this drug. Evidence To Decision Only in research settings We recommend not to use fluvoxamine, except in the context of a clinical trial (recommended only in research settings). • Several therapeutic options are recommended for patients with non-severe COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. • For choosing between the therapeutic options, see Section 6.1 and the decision support tool, which displays benefits and harms of the options. New In patients with non-severe COVID-19, fluvoxamine probably has little or no effect on mortality and may have little or no effect on mechanical ventilation and hospitalization, with no data reported for time to symptom resolution and adverse Benefits and harms Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 13 of 142 Justification When moving from evidence to the recommendation not to use fluvoxamine in patients with non-severe COVID-19 except in the context of a clinical trial, the GDG emphasized the lack of a clear mechanism of action and the low certainty evidence suggesting little to no effect on hospitalization and mechanical ventilation, moderate certainty evidence of little or no effect on mortality, as well as the absence of reliable data on serious adverse effects attributable to the drug known for significant pharmacological interactions. The panel noted that in the largest trial more patients discontinued the investigational product in the fluvoxamine group than in the placebo group. Noting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did not anticipate important variability in patient values and preferences. The panel also did not believe that other considerations, such as resource considerations, accessibility, feasibility, and equity (see summary of these factors under Evidence to Decision) impacted this specific recommendation. Applicability Special populations: None of the included studies enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did not see a reason to assume that children with COVID-19 would respond any differently to treatment with fluvoxamine. effects leading to drug discontinuation. The GDG concluded that the balance between benefits and potential harms does not favour treatment. The planned subgroup analyses for fluvoxamine versus standard care for age and time of symptom onset did not support any differences in relative effects, whereas disease severity could not be performed since trials only enrolled patients with non-severe COVID-19. The evidence summary was informed by 3 trials with 2225 participants included in the LNMA. The largest trial (n=1480) exclusively enrolled patients in Brazil (19). Certainty of evidence was rated as: moderate for mortality (due to serious indirectness), and low for mechanical ventilation (due to serious indirectness, imprecision, and some concerns regarding risk of bias) and hospitalization (due to serious imprecision and risk of bias). Acknowledging that its evaluation of the certainty of the evidence may differ from other published meta-analyses (20), panel members pointed out that early stopping due to apparent benefit may have biased the results of the largest trial. They argued that, although the stopping rules were pre-specified, the decision was based on the effect estimate on a composite outcome of questionable importance, meanwhile the number of important events was lower. The panel also raised concerns regarding the uncertain applicability of this trial conducted in a single country. Certainty of the Evidence Given the agreed upon values and preferences statement (see Section 7), the GDG inferred that almost all well-informed patients would choose not to receive fluvoxamine therapy for COVID-19 based on the available evidence. The GDG did not believe that other considerations, such as feasibility, acceptability, equity and cost, would impact this specific recommendation. Specifically, the GDG did not consider the potential role of fluvoxamine as an antidepressant for this guideline of medications for COVID-19. Values and preferences The panel acknowledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which could limit their availability in resource-constrained areas. However, although fluvoxamine is relatively inexpensive, compared with other drugs used for COVID-19, and widely available, including in low-income settings, the evidence does not justify the use of fluvoxamine for non-severe COVID-19 anywhere. Although the cost of fluvoxamine may be low, the GDG panel raised concerns regarding the risk of diverting attention and resources away from interventions that are more likely to provide a benefit. To avoid the risk of writing recommendations that would risk perpetuating and legitimizing unequal access to more effective drugs, the panel believed that it would be preferable to emphasize the need for more equitable access to effective therapeutic options. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 14 of 142 Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: No fluvoxamine Summary The LNMA for fluvoxamine was informed by three RCTs which enrolled 2225 patients with non-severe illness in outpatient settings. All three RCTs were registered, and two were published in a peer-reviewed journal. All three studies were conducted in outpatients. None of the included studies enrolled children. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of fluvoxamine compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Based on data from the TOGETHER trial (19), no credible subgroup effects were observed on the primary outcome by age (children vs adults vs older adults) and time from symptom onset (0–3 days vs 4–7 days). Planned subgroup analyses for disease severity, age and chronic conditions (absolute effects), serological status and vaccination status were precluded by lack of available data. Outcome Timeframe Study results and measurements Comparator No fluvoxamine Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.68 (CI 95% 0.33 — 1.32) Based on data from 1649 participants in 2 studies. (Randomized controlled) 4 per 1000 Difference: 3 per 1000 1 fewer per 1000 ( CI 95% 3 fewer — 1 more ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation Odds ratio 0.73 (CI 95% 0.38 — 1.4) Based on data from 1649 participants in 2 studies. (Randomized controlled) 18 per 1000 Difference: 13 per 1000 5 fewer per 1000 ( CI 95% 11 fewer — 7 more ) Low Due to serious indirectness and imprecision 2 There may be little or no difference in mechanical ventilation Hospital admission High risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 35 per 1000 Difference: 25 per 1000 10 fewer per 1000 ( CI 95% 23 fewer — 8 more ) Low Due to very serious imprecision 3 Fluvoxamine may reduce hospitalization Hospital admission Higher risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 60 per 1000 Difference: 43 per 1000 17 fewer per 1000 ( CI 95% 39 fewer Low Due to very serious imprecision 4 Fluvoxamine may reduce hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 15 of 142 — 13 more ) Outcome Timeframe Study results and measurements Comparator No fluvoxamine Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: serious. 3. Imprecision: very serious. The credible interval includes both important harm and important benefit.. 4. Imprecision: very serious. The credible interval includes both important harm and important benefit. 5. Imprecision: very serious. The credible interval includes both important harm and important benefit. Hospital admission Highest risk Odds ratio 0.7 (CI 95% 0.34 — 1.23) Based on data from 2196 participants in 3 studies. (Randomized controlled) 100 per 1000 Difference: 72 per 1000 28 fewer per 1000 ( CI 95% 64 fewer — 20 more ) Low Due to very serious imprecision 5 Fluvoxamine may reduce hospitalization Adverse effects leading to drug discontinuation No data The effect of fluvoxamine is unknown Time to symptom resolution No data The effect of fluvoxamine is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 0 per 1000 Difference: 3 per 1000 3 more per 1000 ( CI 95% 1 more — 5 more ) Very low Due to serious indirectness, imprecision, and serious risk of bias 1 The impact on mortality is very uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 16 of 142 Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. The EPIC-HR study was stopped early for benefit. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: serious. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study (EPIC-HR) was stopped early for benefit. Imprecision: serious. Mechanical ventilation No data 2 The effect on mechanical ventilation is unknown Hospital admission Odds ratio 4.54 (CI 95% 1.32 — 12.78) (Randomized controlled) 5 per 1000 Difference: 22 per 1000 17 more per 1000 ( CI 95% 2 more — 55 more ) Low Due to serious imprecision and risk of bias 3 Nirmatrelvir-ritonavir may reduce hospitalization more than fluvoxamine Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 5.74 (CI 95% 0.95 — 56.11) (Randomized controlled) 0.4 per 1000 2 per 1000 Low Due to serious indirectness and There may be little or no difference in mortality Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 17 of 142 imprecision 1 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: very serious. 3. Imprecision: very serious. The credible interval includes both important harm and important benefit. Difference: 1.6 more per 1000 ( CI 95% 0.02 fewer — 21.56 more ) Mechanical ventilation Odds ratio 1.77 (CI 95% 0.19 — 10.6) (Randomized controlled) 8 per 1000 Difference: 14 per 1000 6 more per 1000 ( CI 95% 6 fewer — 71 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect on mechanical ventilation is uncertain Hospital admission Odds ratio 1.31 (CI 95% 0.52 — 2.98) (Randomized controlled) 19 per 1000 Difference: 25 per 1000 6 more per 1000 ( CI 95% 9 fewer — 36 more ) Low Due to very serious imprecision 3 There may be little or no difference in hospital admission Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Fluvoxamine Comparator: Remdesivir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 18 of 142 6.2.1 Mechanism of action Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) approved as an antidepressant. The antidepressant effects of fluvoxamine are related to inhibition of the serotonin transporter in the brain, which serves to increase the concentrations of serotonin in the synaptic cleft. In COVID-19, several putative anti-inflammatory or antiviral mechanisms of action have been proposed (21)(22). First, anti-inflammatory properties have been postulated as a result of serotonin transporter inhibition in Outcome Timeframe Study results and measurements Comparator Remdesivir Intervention Fluvoxamine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, it is plausible that fluvoxamine may have an important impact on mortality. Imprecision: serious. There were very few events. 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. Imprecision: very serious. 3. Imprecision: very serious. Mortality Odds ratio 0.87 (CI 95% 0.27 — 2.85) (Randomized controlled) 3 per 1000 Difference: 3 per 1000 0 fewer per 1000 ( CI 95% 2 fewer — 6 more ) Low Due to serious indirectness and serious imprecision 1 There may be little or no difference in mortality Mechanical ventilation Odds ratio 1.63 (CI 95% 0.19 — 11.23) (Randomized controlled) 8 per 1000 Difference: 13 per 1000 5 more per 1000 ( CI 95% 6 fewer — 75 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect on mechanical ventilation is uncertain Hospital admission Odds ratio 2.76 (CI 95% 0.62 — 12.07) (Randomized controlled) 9 per 1000 Difference: 24 per 1000 15 more per 1000 ( CI 95% 3 fewer — 90 more ) Low Due to very serious imprecision 3 Remdesivir may reduce hospitalization more than fluvoxamine Adverse effects leading to drug discontinuation No data The effect on adverse effects is unknown Time to symptom resolution No data The effect on time to symptom resolution is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 19 of 142 platelets and/or lungs, but this is based upon indirect evidence from non-COVID-19 disease models. Secondly, host-directed antiviral properties have been proposed via agonism of the sigma-1 receptor, for which some evidence exists from other viruses for an involvement in RNA replication, but there are currently no published preclinical studies that directly demonstrate or refute a mechanism in COVID-19. Therefore, plausibility requires interpretation of indirect evidence for anti-inflammatory or antiviral mechanisms, which are currently unproven preclinically and not directly related to the mechanism and site of action in depression. 6.3 Colchicine (published 14 July 2022) For patients with non-severe COVID-19 Practical Info The GDG made a strong recommendation against using colchicine for treatment of patients with non-severe COVID-19 and therefore practical considerations are less relevant. Evidence To Decision Strong recommendation against We recommend against treatment with colchicine (strong recommendation against). • Several therapeutic options are recommended for patients with non-severe COVID-19 including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. • For choosing between the therapeutic options, see Section 6.1 and the decision support tool, which displays benefits and harms of the options. New In patients with non-severe COVID-19, colchicine probably has little or no impact on mortality and mechanical ventilation, may have little or no impact on hospitalizations, and may increase the likelihood of adverse effects leading to drug discontinuation. The panel discussed the risk of drug interactions and colchicine's narrow therapeutic window, particularly in patients with or at risk of hepatic and renal failure. Colchicine toxicity can be severe, and sometimes fatal. The planned subgroup analyses for colchicine versus standard care did not show different relative effects for disease severity, and age (children, adults, older) with no data reported from illness onset. Benefits and harms The evidence summary on colchicine was informed by a systematic review including 13 trials with 18 172 participants. The evidence was most abundant for mortality with incomplete reporting for other outcomes (e.g. five trials with 598 participants for adverse effects). A single trial of 4488 participants (23), which contributed almost all of the evidence on hospitalizations, was stopped prematurely. Certainty of evidence was rated as: moderate for mortality and mechanical ventilation (rated down for indirectness); low for admission to hospital (rated down for imprecision and risk of bias); and low for adverse effects leading to drug discontinuation (rated down for imprecision and risk of bias). Certainty of the Evidence Given the agreed upon values and preferences statement (see Section 7), the GDG inferred that almost all well-informed patients would choose not to receive colchicine based on available evidence regarding relative benefits and harms. The GDG did not believe that other considerations, such as feasibility, acceptability, equity, and cost, impacted this specific recommendation. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 20 of 142 Justification When moving from evidence to the strong recommendation against the use of colchicine for patients with non-severe COVID-19, the GDG emphasized the moderate certainty evidence of no effect on mortality and mechanical ventilation, and the low certainty evidence of no effect on hospitalizations, but possible harm associated with treatment. Specifically, the panel recognized the risks of diarrhoea, cytopenia, and other toxicities, particularly among patients with, or at risk of, renal failure, as potentially important to patients with non-severe COVID-19. Noting that effective therapeutic alternatives exist for non-severe COVID-19, the GDG did not anticipate important variability in patient values and preferences. The panel also did not believe that other considerations, such as resource considerations, accessibility, feasibility, and equity (see summary of these factors under Evidence to Decision) impacted this specific recommendation. Applicability Special populations: None of the included studies enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel did not see a reason to assume that children with COVID-19 would respond any differently to treatment with colchicine. The panel acknowledged that effective therapeutic alternatives for non-severe COVID-19 were expensive, which could limit their availability in resource-constrained areas. However, although colchicine is relatively inexpensive, compared with other drugs used for COVID-19, and widely available, including in low-income settings, the evidence does not justify the use of colchicine for non-severe COVID-19 anywhere. Although the cost of colchicine may be low, the GDG raised concerns regarding the risk of diverting attention and resources away from interventions that are more likely to provide a benefit. To avoid writing recommendations that would risk perpetuating and legitimizing unequal access to more effective drugs, the panel believed that it would be preferable to emphasize the need for more equitable access to effective therapeutic options. Resources and other considerations Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Colchicine Comparator: Standard care Summary The systematic review for colchicine included 13 trials that enrolled 18 172 patients. All but three trials were registered. None of the studies enrolled children. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of colchicine compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Based on data from the COLCORONA trial (23), no credible subgroup effects were observed on the primary outcome by age (children vs adults vs older adults) and disease severity (non-severe vs severe). Planned subgroup analyses for time from symptom onset, age and chronic conditions (absolute effects), serological status and vaccination status were precluded by lack of available data. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Colchicine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.84 (CI 95% 0.5 — 1.17) Based on data from 17 914 participants in 10 studies. (Randomized 4 3 Moderate Due to serious indirectness 1 Colchicine probably has little or no impact on mortality Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 21 of 142 per 1000 per 1000 controlled) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Colchicine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. 2. Indirectness: serious. Imprecision: no serious. Credible interval includes modest benefit. 3. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 4. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 5. Imprecision: very serious. 6. Risk of bias: serious. Imprecision: serious. ( CI 95% 2 fewer — 1 more ) Mechanical ventilation Odds ratio 0.75 (CI 95% 0.37 — 1.26) Based on data from 12 746 participants in 5 studies. (Randomized controlled) 9 per 1000 Difference: 7 per 1000 2 fewer per 1000 ( CI 95% 6 fewer — 2 more ) Moderate Due to serious indirectness 2 Colchicine probably has little or no impact on mechanical ventilation Admission to hospital Risk in trials Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 35 per 1000 Difference: 24 per 1000 11 fewer per 1000 ( CI 95% 25 fewer — 19 more ) Moderate Due to serious imprecision 3 Colchicine probably has little or no impact on hospital admission Admission to hospital Higher risk Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 60 per 1000 Difference: 42 per 1000 18 fewer per 1000 ( CI 95% 43 fewer — 31 more ) Moderate Due to serious imprecision 4 Colchicine probably has little or no impact on hospital admission Admission to hospital Highest risk Odds ratio 0.68 (CI 95% 0.27 — 1.57) Based on data from 4949 participants in 3 studies. (Randomized controlled) 100 per 1000 Difference: 70 per 1000 30 fewer per 1000 ( CI 95% 71 fewer — 49 more ) Low Due to very serious imprecision 5 Colchicine may have little or no impact on hospital admission Adverse effects leading to drug discontinuation Based on data from 598 participants in 5 studies. (Randomized controlled) 0 per 1000 Difference: 34 per 1000 34 more per 1000 Low Due to serious risk of bias and serious imprecision 6 Colchicine may increase the risk of adverse effects leading to drug discontinuation Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 22 of 142 Difference: 1 fewer per 1000 6.3.1 Mechanism of action Colchicine is an anti-inflammatory drug used to treat gout, recurrent pericarditis, familial Mediterranean fever, and other inflammatory indications. There are several proposed mechanisms of action that are theorized to obviate inflammation- associated pathology seen in COVID-19 (24)(25), which include a reduction in chemotaxis of neutrophils, inhibition of inflammasome signalling, and decreased production of cytokines such as interleukin-1b (IL-1b). There are no published data at the time when the guideline was pubished from animal models of SARS-CoV-2 infection to support or refute pre-clinical efficacy or harm of colchicine in associated disease pathology. The mechanism of action is postulated to be similar to that for the indications for which colchicine is already approved, but plausibility of effect in COVID-19 requires assumptions around similarities between COVID-19 and other diseases to be accepted. There are marked differences between trials in terms of the doses and schedules that have been investigated in COVID-19. Within the studies included in the NMA, doses ranged between 0.5 and 2 mg per day, course durations ranged between 6 and 30 days, some studies used once daily dosing, some used twice daily dosing, and others used three times daily dosing. In addition, some studies used dosing schedules which changed throughout the course, starting with one dose or schedule and then changing to a different dose or schedule after a predetermined interval. The pharmacokinetics of colchicine are dose linear between 0.5 mg and 1.5 mg (26)(27) but the substantive variation between studies included in the NMA precludes a robust interpretation of differences in outcome associated with dose and schedule. 6.4 Nirmatrelvir-ritonavir (published 22 April 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (nirmatrelvir-ritonavir for COVID-19, administration of nirmatrelvir-ritonavir for COVID-19, safety and monitoring for patients receiving nirmatrelvir- ritonavir for COVID-19). Here follows a brief summary of key points: • The recommended dose for nirmatrelvir-ritonavir is 300 mg (two 150 mg tablets) of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days, as per the regimen evaluated in large trials informing the recommendation. • In renal insufficiency (GFR 30–59 mL/min) the dose reduction is 150 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours daily for 5 days. Info Box Recommendations concerning nirmatrelvir-ritonavir for patients with non-severe COVID-19 were published on 22 April 2022 as the tenth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of two RCTs, as per the LNMA on drug therapies (1). No changes were made for the nirmatrelvir-ritonavir recommendation in this eleventh version of the guideline. Strong recommendation for We recommend treatment with nirmatrelvir-ritonavir (strong recommendation for). • See Section 6.1 for help to identify patients at highest risk. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and monoclonal antibodies. • The GDG concluded that nirmatrelvir-ritonavir represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • The strong recommendation in favour does not apply to pregnant women, children, or those with possible dangerous drug interactions (many drugs interact with nirmatrelvir-ritonavir, see mechanism of action). • Nirmatrelvir-ritonavir should be administered as soon as possible after onset of symptoms, ideally within 5 days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 23 of 142 • Administration should be as early as possible in the time course of the disease. In the included studies, nirmatrelvir-ritonavir was administered within 5 days of disease onset. • The GDG concluded that nirmatrelvir-ritonavir should not be offered to children, breastfeeding or pregnant women with COVID-19. In any patient being considered for nirmatrelvir-ritonavir use, clinicians need to give serious consideration to drug interactions. The Liverpool COVID-19 drug interaction checker may be useful in this regard (28). Evidence To Decision In highest risk patients in whom an appreciable decrease in hospitalization with nirmatrelvir-ritonavir is likely, the benefits clearly outweigh the harms, thus warranting the strong recommendation in favour of the drug. In patients with non-severe COVID-19, nirmatrelvir-ritonavir likely reduces admission to hospital (moderate certainty evidence). It may have little or no impact on mortality (low certainty evidence). There are no data reported for time to symptom resolution or mechanical ventilation. Treatment does not increase the likelihood of adverse effects leading to drug discontinuation (high certainty evidence), though diarrhoea and dysgeusia (loss of taste) have occurred more frequently with nirmatrelvir-ritonavir as compared with placebo. The GDG acknowledged that there was a paucity of information relating to emergence of resistance and much more data were needed to inform the recommendation. Benefits and harms The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC-HR) with 3100 participants included in the LNMA study (1)(29)(30). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to concerns regarding imprecision and risk of bias); low for mortality (rated down due to serious imprecision and indirectness) and high for adverse effects leading to drug discontinuation. We did not rate the certainty of the evidence for diarrhoea and dysgeusia. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (31). Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a higher risk of hospitalization would choose to use nirmatrelvir-ritonavir. Values and preferences Acceptability and feasibility Nirmatrelvir-ritonavir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that nirmatrelvir-ritonavir be reserved for those at higher risk. Obstacles to access in low- and middle-income countries (LMICs) may prove formidable due to cost and availability. Those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments, in the first 5 days of symptoms, and thus less access to the interventions. Therefore, if patients at higher risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 24 of 142 Justification Moderate certainty evidence of a substantial relative risk reduction in hospitalization, and high certainty evidence of no adverse effects requiring drug discontinuation, motivated the strong recommendation in individuals at higher risk of hospitalization. Such individuals are likely to achieve an important reduction in the absolute risk of hospitalization in comparison with those not receiving nirmatrelvir-ritonavir. Alternative or combination therapy The GDG has previously made a conditional recommendation for molnupiravir (see Section 6.6) in the highest risk non-severe population, and in this guideline update a conditional recommendation for remdesivir (see Section 6.5). Indirect comparisons in higher and highest risk patients found nirmatrelvir-ritonavir may reduce hospitalization when compared with molnupiravir (low certainty); however, found little or no difference when compared with remdesivir (low certainty). Without direct data comparisons and low certainty confidence in indirect comparisons, the GDG chose not to make comparative recommendations between drugs, but rather remark that nirmatrelvir-ritonavir may be superior based on its efficacy compared with standard of care (moderate certainty) and then ultimate choice based on practical issues, such as ease of administration and risk profiles. There is no evidence for combining antiviral therapies; the GDG therefore advised against this. Applicability The applicability of this recommendation to children, breastfeeding and pregnant women is currently uncertain, as the included RCTs enrolled only non-pregnant adults. The GDG concluded that nirmatrelvir-ritonavir should not be offered to children, breastfeeding or pregnant women with COVID-19. Prequalification Unit. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options according Access to SARS-CoV-2 diagnostics: Since this recommendation involves ideally administering treatment with nirmatrelvir- ritonavir within 5 days of symptom onset, increasing access and ensuring appropriate use of diagnostic tests is essential for implementation. Thus, availability and use of appropriate SARS-CoV-2 diagnostic tests is needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of rapid diagnostic tests such as antigen-detection assays can improve early diagnosis in the community and in primary health care settings. Health care systems must, however, gain expertise in choosing and implementing rapid tests, choosing those most applicable to their settings. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: No nirmatrelvir-ritonavir Summary The LNMA for nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which enrolled 3100 patients with non-severe illness in outpatient settings. The two RCTs were registered; and one was published in a peer-reviewed journal (30). None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and were randomized within 5 days of symptom onset, and no patients received therapeutic co-interventions, these subgroup analyses could not be performed. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 25 of 142 Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0.04 (CI 95% 0 — 0.67) Based on data from 3100 participants in 2 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 2 fewer ) Low Due to serious imprecision and indirectness 1 Nirmatrelvir-ritonavir may have a small effect on mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 35 per 1000 Difference: 5 per 1000 30 fewer per 1000 ( CI 95% 33 fewer — 21 fewer ) Moderate Due to concerns with risk of bias and imprecision 2 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Higher risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 60 per 1000 Difference: 9 per 1000 51 fewer per 1000 ( CI 95% 56 fewer — 36 fewer ) Moderate Due to concerns with risk of bias and imprecision 3 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 100 per 1000 Difference: 16 per 1000 84 fewer per 1000 ( CI 95% 93 fewer — 59 fewer ) Moderate Due to concerns with risk of bias and imprecision 4 Nirmatrelvir-ritonavir probably reduces hospitalization Adverse effects leading to drug discontinuation Odds ratio 0.48 (CI 95% 0.29 — 0.8) Based on data from 2246 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 26 of 142 1. Indirectness: serious. Some patients may be at substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 events (all in the placebo group); and only one study. 2. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0 (CI 95% 0 — 0.29) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 19 per 1000 Difference: 6 per 1000 13 fewer per 1000 ( CI 95% 17 fewer — 2 fewer ) Low Due to risk of bias and imprecision 2 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 57 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 3 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 33 per 1000 17 per 1000 Low Due to risk of bias and imprecision 4 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 27 of 142 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. 2. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 1000 ( CI 95% 51 fewer — 6 fewer ) Adverse effects leading to drug discontinuation 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High There is little or no difference in the risk of adverse effects leading to drug discontinuation. Time to symptom resolution No data The effect of nirmatrelvir/ritonavir is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 28 of 142 Difference: 40 fewer per Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 29 of 142 For patients with non-severe COVID-19 at low risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in a summary of practical issues. In any patient being considered for nirmatrelvir-ritonavir use, clinicians need to give serious consideration to drug interactions. The Liverpool COVID-19 drug interaction checker may be useful in this regard (28). Evidence To Decision Justification Most patients who contract COVID-19 are at very low risk of hospitalization (under 1%) and at a vanishingly small risk of mortality. Such patients will experience trivial benefits with use of nirmatrelvir-ritonavir. The panel inferred that most such Conditional recommendation against We suggest not to use treatment with nirmatrelvir-ritonavir (conditional recommendation against). • In the GDG's assessment, only a minority of low-risk patients will choose to consider using nirmatrelvir-ritonavir. • Trials on antivirals included patients with some risk factors for hospital admission, resulting in a baseline risk of 3% that the GDG applied to generate the recommendation. The risk of hospitalization is likely to be lower in the general population. • Clinicians should not consider nirmatrelvir-ritonavir in pregnant women, children, or those with possible dangerous drug interactions (note: many drugs interact with nirmatrelvir-ritonavir). In patients with non-severe COVID-19, nirmatrelvir-ritonavir probably reduces admission to hospital. However, in low risk patients, the absolute benefit is very small and unlikely to be important to most patients. Nirmatrelvir-ritonavir probably has little or no impact on mortality. Highly relevant to patients at low risk of hospitalization, studies have reported no data for time to symptom resolution. EPIC-SR did, however, report a very closely related outcome: time to 4 consecutive days of mild or no symptoms. For this analysis, the median time was 13.0 (95% CI 12 to 15) days for nirmatrelvir-ritonavir, and 13.0 (95% CI 11 to 14) days for placebo (p=0.47). Treatment does not increase the likelihood of adverse effects leading to drug discontinuation, though diarrhoea and dysgeusia have occurred more frequently with nirmatrelvir-ritonavir, as compared with placebo. Benefits and harms The evidence summary on nirmatrelvir-ritonavir was informed by two trials (EPIC-SR and EPIC HR) with 3100 participants included in the LNMA study (1)(29)(30). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to concerns regarding serious imprecision and risk of bias); low for mortality (rated down due to serious imprecision and indirectness) and high for adverse effects leading to drug discontinuation. We did not rate certainty of evidence for diarrhoea and dysgeusia. Certainty of the Evidence The GDG believes that most low risk patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on outcomes they consider important. This consideration is particularly relevant for shortening of the duration of symptoms, for which we have no direct evidence supporting a positive impact of nirmatrelvir-ritonavir. Values and preferences Nirmatrelvir-ritonavir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that nirmatrelvir-ritonavir be reserved for those at highest risk. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 30 of 142 patients would be uninterested in using the drug for these trivial benefits. Thus, for most patients, sufficient risk - and thus sufficient benefit of nirmatrelvir-ritonavir - to make nirmatrelvir-ritonavir use an attractive option will require presence of at least one if not a combination of risk factors. This is particularly true in low-income settings in which resource constraints and feasibility issues will make nirmatrelvir-ritonavir use less attractive. The GDG, nevertheless, was cognizant that there are likely to be an appreciable number of individuals who place a high value on very small reductions in the risk of hospitalization and who would thus choose use of nirmatrelvir-ritonavir; therefore, a conditional rather than strong recommendation was made. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: No nirmatrelvir-ritonavir Summary The LNMA for nirmatrelvir-ritonavir was informed by two RCTs (EPIC-SR and HR) which enrolled 3100 patients with non-severe illness in outpatient settings. The two RCTs were registered; and one was published in a peer-reviewed journal (30). None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of nirmatrelvir-ritonavir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age (children were not enrolled). As all patients were unvaccinated and were randomized within 5 days of symptom onset, and no patients received therapeutic co-interventions, these subgroup analyses could not be performed. Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0.04 (CI 95% 0 — 0.67) Based on data from 3100 participants in 2 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 2 fewer ) Low Due to serious imprecision and indirectness 1 Nirmatrelvir-ritonavir may have a small effect on mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 35 per 1000 Difference: 5 per 1000 30 fewer per 1000 ( CI 95% 33 fewer — 21 fewer ) Moderate Due to concerns with risk of bias and imprecision 2 Nirmatrelvir-ritonavir probably reduces hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 31 of 142 Outcome Timeframe Study results and measurements Comparator No nirmatrelvir- ritonavir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. Nirmatrelvir-ritonavir probably reduces mortality in these patients. Imprecision: serious. There were only 12 events (all in the placebo group); and only one study. 2. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Admission to hospital Higher risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 60 per 1000 Difference: 9 per 1000 51 fewer per 1000 ( CI 95% 56 fewer — 36 fewer ) Moderate Due to concerns with risk of bias and imprecision 3 Nirmatrelvir-ritonavir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.15 (CI 95% 0.06 — 0.38) Based on data from 3078 participants in 2 studies. (Randomized controlled) 100 per 1000 Difference: 16 per 1000 84 fewer per 1000 ( CI 95% 93 fewer — 59 fewer ) Moderate Due to concerns with risk of bias and imprecision 4 Nirmatrelvir-ritonavir probably reduces hospitalization Adverse effects leading to drug discontinuation Odds ratio 0.48 (CI 95% 0.29 — 0.8) Based on data from 2246 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High Nirmatrelvir-ritonavir has little or no risk of adverse effects leading to drug discontinuation Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Nirmatrelvir-ritonavir Comparator: Molnupiravir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 32 of 142 Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Nirmatrelvir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Odds ratio 0 (CI 95% 0 — 0.29) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) Moderate Due to serious indirectness 1 There is probably little or no difference in mortality Mechanical ventilation No data The effect of nirmatrelvir-ritonavir is unknown Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 19 per 1000 Difference: 6 per 1000 13 fewer per 1000 ( CI 95% 17 fewer — 2 fewer ) Low Due to risk of bias and imprecision 2 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 57 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 3 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.1 — 0.88) (Randomized controlled) 33 per 1000 Difference: 17 per 1000 40 fewer per 1000 ( CI 95% 51 fewer — 6 fewer ) Low Due to risk of bias and imprecision 4 Nirmatrelvir-ritonavir may reduce hospitalization more than molnupiravir Adverse effects leading to drug discontinuation 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 0 fewer ) High There is little or no difference in the risk of adverse effects leading to drug discontinuation. Time to symptom resolution No data The effect of nirmatrelvir/ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 33 of 142 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. 2. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 3. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. 4. Risk of bias: serious. The nirmatrelvir-ritonavir study was stopped early for benefit. Imprecision: serious. The total sample size does not meet the optimal information size. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 34 of 142 6.4.1. Mechanism of action Nirmatrelvir inhibits the SARS-CoV-2 protease (3CLpro), thereby preventing cleavage of the viral polyprotein which is needed for viral proteins to become functional (32). Inhibition of the protease renders the virus unable to replicate. Nirmatrelvir is co- administered with ritonavir, a HIV protease inhibitor, used in this context to boost the pharmacokinetics of nirmatrelvir but without exerting any direct antiviral activity itself (33). Therefore, the combination should be considered as antiviral monotherapy. Nirmatrelvir was developed as an orally deliverable analogue of an intravenous prodrug (lufotrelvir; PF-07304814). The drug was originally developed for SARS-CoV, and has been subsequently repurposed for SARS-CoV-2. Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 in differentiated normal human bronchial epithelial cells with an EC50 of 0.06 micromolar and an EC90 of 0.18 micromolar (33). In healthy volunteers, plasma maximum concentrations of nirmatrelvir were 2210 ng/mL with a half-life of 6 hours following a 300/100 mg dose of nimatrelvir-ritonavir, and steady-state pharmacokinetics were achieved on day 2 (34) (an EC90 of 0.18 micromolar equates to approximately 90 ng/mL). High doses (300 mg/kg) of unboosted nimatrelvir was active against murine-adapted SARS-CoV-2 in mice but with maximum concentrations higher than those achieved at 300/100 mg doses in healthy human volunteers (33). High doses (250 mg/kg) of unboosted nimatrelvir also had efficacy in SARS-CoV-2-infected Syrian golden hamsters but no pharmacokinetic data are available in this species (35). Based upon genome sequence of Omicron, there appears to be no molecular basis for a loss of activity. Nimatrelvir retains activity against BA.1 Omicron in vitro (36) but in vivo data are currently unavailable. Much more data are required to ascertain the rate at which resistance will emerge for nirmatrelvir. Single amino acid changes introduced into the protease sequence can reduce activity of nirmatrelvir by between 23.6- and 39-fold (34). Mouse hepatitis virus (used as a betacoronavirus surrogate) acquired several mutations under a selective pressure in vitro, and these reduced nirmatrelvir activity by between 4- and 91-fold (34). Two amino substitutions were described in clinical trials, one of which did not impact nirmatrelvir activity. Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 35 of 142 Through its impact on metabolism and clearance, ritonavir is a perpetrator of many drug-drug interactions that will require careful consideration. Short durations of therapy needed in COVID-19 may make drug interactions easier to manage than they are for HIV, but twice daily administration means that the ritonavir dose is double that used in most modern antiretroviral regimens. The impact of ritonavir on metabolism may also outlast dosing by several days. The Liverpool COVID-19 drug interaction checker may constitute a valuable tool for management of drug interactions with nirmatrelvir-ritonavir (28). 6.5 Remdesivir (published 22 April 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (remdesivir for COVID-19, administration of remdesivir for COVID-19, safety and monitoring in patients receiving remdesivir for COVID-19). Here follows a brief summary of the key points: • The recommended dose for remdesivir is one dose daily for 3 consecutive days as intravenous infusion, as per the regimen evaluated in large trials informing the recommendation. Remdesivir is given as 200 mg intravenously on day 1, followed by 100 mg intravenously on days 2 and 3. • Administration should be as early as possible in the time course of the disease. In the included studies, remdesivir was administered within 7 days of disease onset. • It may be reasonable to monitor patients for a brief period following infusion. Any health care workers administering the infusions should follow recommended infection prevention and control recommendations in the outpatient setting. • One should use caution when administering remdesivir to patients with significant liver or kidney disease. • The GDG noted that trials did not enrol children 12 years of age or less with < 40 kg, and thus its use in these children is not recommended. • Additionally, the trials did not enrol pregnant or breastfeeding women. The decision regarding use of this therapeutic should be made between the pregnant person and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and WHO information sheet). Info Box An initial conditional recommendation was made on 20 November 2020, suggesting not to use remdesivir for patients with COVID-19, regardless of illness severity. This was based on data from four RCTs which were available at the time, with 7333 participants hospitalized for COVID-19. In the tenth iteration of the guideline, a new recommendation was made for the use of remdesivir for patients with non-severe illness, The recommendation for patients with severe or critical COVID-19 is under review to be updated shortly. No changes were made to the remdesivir recommendation in this eleventh version of the guideline. Conditional recommendation for We suggest treatment with remdesivir (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk for hospitalization. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies. • The GDG concluded that nirmatrelvir-ritonavir represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • Remdesivir should be administered as soon as possible after onset of symptoms, ideally within 7 days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 36 of 142 Evidence To Decision In patients with non-severe COVID-19, remdesivir probably reduces admission to hospital and and may have little or no impact on mortality. The effect of remdesivir on mechanical ventilation and time to symptom resolution is very uncertain. Treatment probably does not increase the likelihood of adverse effects leading to drug discontinuation. The balance between benefits and potential harms favours treatment, but only in the highest risk group. This is because absolute benefit of remdesivir on hospital admission depends on a given patient's prognosis. The GDG defined a threshold of a 6% absolute reduction in hospital admission to represent what most patients would value as an important benefit. Remdesivir would exert such a benefit in patients at highest risk of hospitalization (above 10% baseline risk), such as older people, or those with immunodeficiencies and/or chronic diseases, further enhanced by lacking vaccination. The conditional recommendation for the use of remdesivir in those at highest risk (above 10% baseline risk) reflects this threshold: 73 fewer hospitalizations per 1000 patients. The planned subgroup analyses for remdesivir versus standard care including age, time of symptom onset and disease severity could not be performed in the absence of subgroup data reported publicly or provided by investigators. There were eight children (12 years or more of age) enrolled in the PINETREE trial (37); however, none died or were hospitalized. Benefits and harms The evidence summary was informed by 5 trials with 2709 participants included in the LNMA, with one trial informing the outcome of hospital admission (1)(37). Certainty of evidence was rated as: moderate for decreased admission to hospital (due to serious imprecision); low for mortality (due to serious imprecision and indirectness); very low for mechanical ventilation (due to extremely serious imprecision and serious risk of bias); and moderate for adverse effects leading to drug discontinuation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (18)(31). See Section 6.1 for more details. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline remdesivir, and only those at highest risk would choose to receive treatment. Values and preferences Acceptability and feasibility Remdesivir is administered as one intravenous infusion daily over 3 consecutive days, representing a feasibility challenge in outpatients aiming to avoid hospital admission. Furthermore, remdesivir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that remdesivir should be reserved for those at highest risk. Obstacles to access in LMICs due to cost, feasibility and availability are of concern (38). Challenges in shared decision- making and in communicating the harms versus benefits of remdesivir may also be increased in LMICs. For example, those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments in the first 7 days of symptoms, and thus less access to the interventions. Therefore, if patients at highest risk receive the intervention, this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 8th invitation to Manufacturers of Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 37 of 142 Justification When moving from evidence to the conditional recommendation to use remdesivir in patients with non-severe COVID-19, the GDG emphasized the benefits on decreased need for hospitalization, along with little or no serious adverse effects attributable to the drug. Feasibility and complexity of administration were also carefully considered, and led to the recommendation for use only in the highest risk patients. Typical characteristics of people at highest risk include older people, or those with immunodeficiencies and/or chronic diseases with being unvaccinated further contributing to risk. Costs and access were important considerations, and the GDG recognizes that this recommendation could exacerbate health inequities. The GDG did not anticipate important variability in patient values and preferences (see Evidence to Decision). Alternative or combination therapy The GDG has previously made a a conditional recommendation for molnupiravir in the highest risk non-severe population, and in this guideline a strong recommendation for nirmatrelvir-ritonavir (see Section 6.2) and a conditional recommendation against nirmatrelvir-ritonavir in the lower risk non-severe population. Indirect comparisons in higher and highest risk patients found remdesivir may reduce hospitalization when compared with molnupiravir (low certainty); and found little or no difference when compared with nirmaltrelvir-ritonanivir (low certainty). Without direct data and low certainty confidence in indirect comparisons the GDG chose not to make comparative recommendations between drugs, but rather remark that nirmatrelvir-ritonavir may be superior based on its efficacy compared with standard of care and that ultimate choice be based on practical issues such as administration and potential drug-drug interactions. There is no evidence for combining antiviral therapies; the GDG therefore advised against this. Applicability Only one of the included trial included children (12 years of age and older), and the numbers were extremely small; therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of remdesivir to pregnant or lactating women. The decision regarding use of this therapeutic should be made between the pregnant individual and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and Practical info tabs). The GDG also had concerns about whether the drug would retain efficacy against emerging variants of concern such as Omicron BA.1 or BA.2. Surveillance is needed for SARS-CoV-2 strains with reduced susceptibility to remdesivir and further research examining the role of combination therapy in severely immunocompromised patients. Until further data are available, we have no reason to believe that activity against known variants will be diminished. therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Pre- qualification Unit. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer treatment with remdesivir within 7n days of symptom onset, increasing access and ensuring appropriate use of diagnostic tests is essential. Thus, availability and use of reliable and timely SARS-CoV-2 diagnostic tests (including the use of nucleic acid amplification tests (NAAT) and antigen-based rapid detection tests (Ag-RDTs)) are needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier access to clinical care, particularly in the community and in primary health care settings. National programmes should optimize their testing systems to reflect local epidemiology, response objectives, available resources and needs of their populations. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: Nirmatrelvir-ritonavir Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 38 of 142 Outcome Timeframe Study results and measurements Comparator Nirmatrelvir- ritonavir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Risk of bias: serious. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. Mortality 28 days 0 per 1000 Difference: 3 per 1000 3 more per 1000 2 more — 5 more Very low Due to serious risk of bias, indirectness, and imprecision 1 The impact on mortality is uncertain Mechanical ventilation No data The impact on mechanical ventilation is unknown Hospital admission Risk in trials Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 6 per 1000 Difference: 9 per 1000 3 more per 1000 ( CI 95% 4 fewer — 38 more ) Low Due to serious risk of bias and imprecision 2 There may be little or no difference in hospital admission Hospital admission Higher risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 9 per 1000 Difference: 15 per 1000 6 more per 1000 ( CI 95% 6 fewer — 55 more ) Low Due to serious risk of bias and imprecision 3 There may be little or no difference in hospital admission Hospital admission Highest risk Odds ratio 1.64 (CI 95% 0.33 — 7.57) (Randomized controlled) 16 per 1000 Difference: 26 per 1000 10 more per 1000 ( CI 95% 11 fewer — 94 more ) Low Due to serious risk of bias and imprecision 4 There may be little or no difference in hospital admission Adverse events leading to drug discontinuation 0 per 1000 9 per 1000 Very low Due to very serious imprecision, serious risk of bias, serious indirectness, and very serious risk of bias 5 The impact on adverse effects leading to drug discontinuation is uncertain Time to symptom resolution No data The effect of nirmatrelvir-ritonavir is unknown Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 39 of 142 control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 3. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 4. Risk of bias: serious. The EPIC-HR study of nirmatrelvir-ritonavir was stopped early for benefit. Imprecision: serious. Credible interval includes no difference and important harm. 5. Risk of bias: very serious. Indirectness: serious. Imprecision: very serious. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Remdesivir Comparator: No remdesivir Summary The LNMA for remdesivir was informed by five RCTs which enrolled 2731 patients with non-severe illness in outpatient settings; data was available for 2710 patients. All RCTs were registered; and four were published in peer-reviewed journals (15)(37)(39)(40). One of the included studies enrolled children 12 years of age and over; none included pregnant women. The Table shows characteristics of the RCTs. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of remdesivir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). The PINETREE trial was the only study to report subgroups within the non-severe subgroup (37). The planned subgroup analyses were limited by available data but did not detect credible subgroup effects for serological status and age. As all patients were unvaccinated, randomized within 7 days of symptom onset, and did not receive therapeutic co- interventions; these subgroup analyses could not be performed. Of note, for age, 1.4% (n=8) were between 12 and 18 years old in the PINETREE trial, and none died or were hospitalized; no subgroup effect was noted for > 60 vs ≤ 60 years old patients (p=0.78). Outcome Timeframe Study results and measurements Comparator No remdesivir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.68 (CI 95% 0.39 — 1.21) Based on data from 2709 participants in 5 studies. (Randomized controlled) 6 per 1000 Difference: 4 per 1000 2 fewer per 1000 4 fewer — 1 more Low Due to serious indirectness and imprecision 1 Remdesivir may have little or no impact on mortality Mechanical ventilation Odds ratio 0.42 (CI 95% 0.08 — 1.96) Based on data from 261 participants in 2 studies. (Randomized controlled) 8 per 1000 Difference: 3 per 1000 5 fewer per 1000 ( CI 95% 7 fewer — 8 more ) Very low Due to very serious imprecision and serious indirectness 2 The impact of remdesivir on mechanical ventilation is uncertain Admission to hospital Risk in trials 35 per 1000 9 per 1000 Moderate Due to serious imprecision 3 Remdesivir probably reduces hospitalization Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 40 of 142 Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. Outcome Timeframe Study results and measurements Comparator No remdesivir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Does not meet optimal information size; few events (50 total events). 2. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. There may be an important difference in mechanical ventilation in these patients. Imprecision: very serious. Credible interval includes important benefit and important harm. Does not meet optimal information size; few events (11 total). 3. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 4. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 5. Imprecision: serious. The total sample size does not meet the optimal information size; few events (23 total events). 6. Imprecision: serious. 7. Imprecision: extremely serious. (Randomized controlled) Difference: 26 fewer per 1000 ( CI 95% 33 fewer — 4 fewer ) Admission to hospital Higher risk Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. (Randomized controlled) 60 per 1000 Difference: 16 per 1000 44 fewer per 1000 ( CI 95% 56 fewer — 7 fewer ) Moderate Due to serious imprecision 4 Remdesivir probably reduces hospitalization Admission to hospital Highest risk Odds ratio 0.25 (CI 95% 0.06 — 0.88) Based on data from 562 participants in 1 study. (Randomized controlled) 100 per 1000 Difference: 27 per 1000 73 fewer per 1000 ( CI 95% 93 fewer — 11 fewer ) Moderate Due to serious imprecision 5 Remdesivir probably reduces hospitalization Adverse effects leading to drug discontinuation Based on data from 1379 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 9 per 1000 9 more per 1000 ( CI 95% 0 more — 21 more ) Moderate Due to serious imprecision 6 There is probably little or no difference in adverse effects leading to drug discontinuation Time to symptom resolution Lower better Based on data from 138 participants in 1 study. (Randomized controlled) 9 days (Median) Difference: 7.2 days (Mean) MD 1.8 fewer ( CI 95% 5.7 fewer — 3.5 more ) Very low Due to extremely serious imprecision 7 The impact of remdesivir on time to symptom resolution is uncertain Clinical Question/ PICO Population: Patients with non-severe COVID-19 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 41 of 142 Intervention: Remdesivir Comparator: Molnupiravir Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 6.55 (CI 95% 1.3 — 53.23) (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 0 fewer — 0 fewer Low Due to serious indirectness and imprecision 1 There may be little or no difference in mortality Mechanical ventilation Odds ratio 1.08 (CI 95% 0.12 — 9) (Randomized controlled) 8 per 1000 Difference: 9 per 1000 1 more per 1000 ( CI 95% 13 fewer — 16 more ) Low Due serious risk of bias and indirectness 2 The there may be little or no difference in mechanical ventilation Admission to hospital Risk in trials Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 19 per 1000 Difference: 9 per 1000 10 fewer per 1000 ( CI 95% 17 fewer — 17 more ) Moderate Due to serious imprecision 3 There may be little or no difference in hospital admission Admission to hospital Higher risk Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 33 per 1000 Difference: 16 per 1000 17 fewer per 1000 ( CI 95% 29 fewer — 29 more ) Low Due to very serious imprecision 4 Remdesivir may reduce hospital admission more than molnupiravir Admission to hospital Highest risk Odds ratio 0.48 (CI 95% 0.11 — 1.93) (Randomized controlled) 57 per 1000 Difference: 28 per 1000 29 fewer per 1000 ( CI 95% 50 fewer — 47 more ) Low Due to very serious imprecision 5 Remdesivir may reduce hospital admission more than molnupiravir Adverse effects leading to drug discontinuation 0 per 1000 Difference: 9 per 1000 9 more per 1000 ( CI 95% 3 fewer — 21 more ) Very low Due to serious risk of bias, imprecision and indirectness 6 The impact on adverse events leading to drug discontinuation is uncertain Time to symptom Lower better (Randomized controlled) 5.6 days (Median) 7.9 days (Mean) Very low Due to extremely serious The impact on time to symptom resolution is very uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 42 of 142 resolution imprecision 7 6.5.1 Mechanism of action Remdesivir was developed for treatment of hepatitis C virus infection, and was also studied in Ebola and Marburg virus infections before being repurposed for SARS-CoV-2. Remdesivir is a nucleoside drug. Its mechanism of action involves chain termination, which is different to lethal mutagenesis: the drug is incorporated preferentially to the endogenous adenosine nucleoside by the SARS-CoV-2 polymerase during replication of the RNA genome. Unlike many other chain-terminating nucleoside drugs used for other viruses, remdesivir elicits delayed chain termination because RNA synthesis is terminated after the addition of three more nucleotides, rather than at the point of remdesivir incorporation (41). Emergence of antiviral resistance: Under a selective pressure in vitro, SAR-CoV-2 resistance to remdesivir emerged and was associated with a mutation (E802D) within the sequence coding for the polymerase (42). The E802D mutation was also reported in a case study describing an immunocompromised patient receiving remdesivir who experienced recrudescence of high-grade viral shedding following a transient virological response to the drug (43). The clinical significance of these observations if remdesivir were widely used in an outpatient setting is unclear. 6.6 Molnupiravir (published 3 March 2022) Outcome Timeframe Study results and measurements Comparator Molnupiravir Intervention Remdesivir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Some patients may be at substantially higher risk of death. There may be an important difference in mortality in these patients. Imprecision: serious. Few events: 50 total events for remdesivir vs. control and 11 events for molnupiravir vs. control. 2. Risk of bias: serious. The evidence for molnupiravir was at high risk of bias. Indirectness: serious. Some patients may be at substantially higher risk of mechanical ventilation. There may be an important difference in mechanical ventilation in these patients. 3. Imprecision: serious. Credible interval includes important benefit and important harm. 4. Imprecision: very serious. Credible interval includes important benefit and important harm. 5. Imprecision: very serious. Credible interval includes important benefit and important harm. 6. Risk of bias: serious. Indirectness: serious. Imprecision: serious. 7. Imprecision: extremely serious. Difference: MD 2.3 more ( CI 95% 1.9 fewer — 7.8 more ) Info Box Recommendations concerning molnupiravir for patients with non-severe COVID-19 were published on 3 March 2022 as the ninth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of six RCTs, as per the LNMA on drug therapies (1). No changes were made to the molnupiravir recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 43 of 142 For patients with non-severe COVID-19 at highest risk of hospitalization (excluding pregnant and breastfeeding women, and children) Practical Info Route, dosage and duration: Additional considerations are available in three summaries of practical issues (molnupiravir for COVID-19, administration of molnupiravir for COVID-19, safety and monitoring for patients receiving molnupiravir for COVID-19). Here follows a brief summary of the key points: • The recommended dose for molnupiravir is 800 mg tablet every 12 hours daily for 5 days, as per the regimen evaluated in large trials informing the recommendation. • Administration should be as early as possible in the time course of the disease. In the included studies, molnupiravir was administered within 5 days of disease onset. Evidence To Decision Conditional recommendation for We suggest treatment with molnupiravir (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk for hospitalization. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies. • The longer-term harms of molnupiravir remain unknown in the absence of clinical evidence, both for individual patients and at the population level. These include genotoxicity, emergence of resistance, and emergence of new variants (see Mechanism of action). • The conditional recommendation reflects the concern for widespread treatment with molnupiravir before more safety data become available. • Use of molnupiravir should be accompanied by mitigation strategies such as avoiding the drug in younger adults, active pharmacovigilance programmes, and monitoring viral polymerase and spike sequences (see Justification). In patients with non-severe COVID-19, molnupiravir probably reduces admission to hospital and time to symptom resolution, and may reduce mortality. The effect of molnupiravir on mechanical ventilation is very uncertain. Treatment does not increase the likelihood of adverse effects leading to drug discontinuation. However, potential long-term harms of molnupiravir remain uncertain and a matter of concern, in the absence of clinical data. Potential harms include emergence of resistance, and the potential harm coming from the risk of molnupiravir-induced mutagenesis. These deliberations (see Justification section) were based on molnupiravir's mechanism of action and available pre-clinical data (see Mechanism of action section). The balance between benefits and potential harms was close, but favoured treatment in the highest risk group, if implemented with other mitigation strategies to avoid harm at individual and population level (see Mitigation strategies section). There is a risk that monotherapy with molnupiravir (as for other antiviral monotherapies) may be associated with emergence of drug resistance, as has been seen with other antivirals (see Mechanism of action section). The absolute benefits of molnupiravir on hospital admission depend on the prognosis. The GDG defined a threshold of a 6% absolute reduction in hospital admission to represent what most patients would value as an important benefit. Molnupiravir would exert such a benefit in patients at highest risk of hospitalization (above 10% baseline risk), such as those that lack COVID-19 vaccination, older people, or those with immunodeficiencies and/or chronic diseases. The conditional recommendation for the use of molnupiravir in those at highest risk reflects this threshold: 60 fewer hospitalizations per 1000 patients, and a greater anticipated absolute survival benefit, although this was not possible to quantify in the absence of data. The planned subgroup analyses could not be performed in the absence of subgroup data reported publicly or provided by investigators. Benefits and harms Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 44 of 142 The evidence summary was informed by six trials with 4796 participants included in the LNMA, including the MOVe-OUT study (44). Certainty of evidence was rated as: moderate for decreased hospitalization (rated down due to serious imprecision); low for mortality (rated down due to serious imprecision and indirectness); moderate for time to symptom resolution (rated down due to serious risk of bias); very low for mechanical ventilation (rated down due to extremely serious imprecision and serious risk of bias); and high for adverse effects leading to drug discontinuation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence (31). In addition, the GDG felt that there was some indirectness because of the possible emergence of variants (including Omicron) for which the effectiveness of currently available monoclonal antibodies may be reduced. The GDG decided against rating certainty down for imprecision for outcomes where low event rates reflected very low baseline risks (e.g. mortality). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline molnupiravir, and only those at highest risk (e.g. unvaccinated, older, or immunosuppressed) would choose to receive treatment. In the absence of research evidence, in a previous survey (see recommendation for casirivimab-imdevimab), the GDG expressed the view that most patients with a risk of hospitalization above 10%, and thus an absolute risk reduction of approximately 6%, would choose to receive treatment, whereas most of those below that risk level would decline treatment. A similar survey was completed by the GDG for this recommendation; the GDG expressed the view that most patients would consider a reduction in the absolute risk of death of 3 per 1000 (increase in survivors from 995 to 998 per 1000 patients) to be important. Values and preferences Acceptability and feasibility Molnupiravir is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This reinforces that molnupiravir should be reserved for those at highest risk. Obstacles to access in LMICs due to cost and availability are of concern (38). Challenges in shared decision-making and in communicating the harms versus benefits of molnupiravir may also be increased in LMICs. For example, those with socioeconomic disadvantages tend to have less access to services, including diagnostic testing and treatments, in the first 5 days of symptoms, and thus less access to the interventions. Therefore, if patients at highest risk receive the intervention this may exacerbate health inequity. It is important that countries integrate the COVID-19 clinical care pathway in the parts of the health system that may provide care for patients with non-severe COVID-19 (i.e. primary care, community care settings). The recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. As an example of this, on 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which included molnupiravir. If this evaluation demonstrates that a product and its corresponding manufacturing (and clinical) site(s) meet WHO recommended standards, it will be included in the list of medicinal products that are considered to be acceptable for procurement by UN organizations and others. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Access to SARS-CoV-2 diagnostics: Since this recommendation emphasizes the need to administer treatment with molnupiravir within 5 days of symptom onset; increasing access and ensuring appropriate use of diagnostic tests is essential. Thus, availability and use of reliable and timely COVID-19 diagnostic tests (including the use of NAAT and Ag-RDTs) is needed to improve access to drugs, especially those targeting the early phase of disease. The appropriate use of Ag-RDTs by individuals and trained professionals can improve early diagnosis and earlier access to clinical care, particularly in the Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 45 of 142 Justification A combination of the evidence, safety concerns based on preclinical data, values and preferences, and feasibility contributed to the conditional recommendation for the use of molnupiravir only in patients with non-severe COVID-19 at highest risk of hospitalization. Typical characteristics of people at highest risk include those who are unvaccinated, older people, or those with immunodeficiencies and/or chronic diseases (e.g. diabetes). Only a minority of patients who are at highest risk are likely to achieve sufficient benefit to compensate for the risks, and other limitations and disadvantages of therapy. These include a lack of reliable tools to identify high-risk patients, limited availability of the drug, and the safety concerns summarized below. • The GDG had concerns about the risk of emergent resistance with a new antiviral deployed as monotherapy (see Mechanism of action section). Significant uncertainty exists regarding how quickly resistance will emerge; in the absence of sufficient clinical data, the GDG concluded large uncertainties remain. • Concerning the risk of the drug promoting the emergence of new variants, the GDG noted that there was a low likelihood that the drug would result in a selective pressure for a new variant; large uncertainty remains in the absence of sufficient clinical data. • Molnupiravir is mutagenic in mammalian cells in vitro, but there is no evidence of mutagenicity in animal models or humans. The GDG therefore acknowledged uncertainty regarding longer term genetic toxicity and potential for malignancy associated with molnupiravir. • Given evidence from rat pups of an impact on growth plate thickness, molnupiravir should not be used in children. Similarly, since molnupiravir elicited embryo-fetal lethality and teratogenicity in offspring when given to pregnant animals, it should not be used in pregnant or breastfeeding women. • The GDG acknowledged that spermatogenesis may also be especially prone to the mutagenic effects of molnupiravir, but that there was uncertainty regarding the consequences to children conceived by fathers receiving or having recently received molnupiravir. Applicability The applicability of this recommendation to children, breastfeeding and pregnant women, is currently uncertain, as the included RCTs enrolled only non-pregnant adults. However, the GDG concluded that molnupiravir should not be offered to children, breastfeeding or pregnant women with COVID-19. In addition, men planning to conceive should be oriented on the potential for temporary genotoxic effect on sperm cell production (see Mitigation strategies section). The unknown long-term risk of genotoxicity is likely to be higher in younger patients as compared with older patients, thus its use in younger adults not a high risk should be avoided. The GDG also had concerns about whether the drug would retain efficacy against emerging variants of concern such as Omicron. While there is no molecular basis for a loss of efficacy, the GDG noted that the higher viral loads and associated disease severity may impact the effectiveness of molnupiravir. This represents another area of uncertainty, given currently available data did not include patients with newer variants, including Omicron (see Section 9). community and in primary health care settings. National programs should optimize their testing systems to reflect local epidemiology, response objectives, available resources and needs of their populations. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Molnupiravir Comparator: Standard care Summary Evidence summary The LNMA for molnupiravir was informed by six RCTs which enrolled 4827 patients with non-severe illness in outpatient settings; the LNMA team had access to data for 4796 patients. All RCTs were registered; none were published in peer-reviewed journals. None of the included studies enrolled children or pregnant women. The appendix Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 46 of 142 summarizes study characteristics and risk of bias ratings, effect estimates by outcome and associated forest plots for molnupiravir versus standard care. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of molnupiravir compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (3). Subgroup analysis Five pre-specified subgroup analyses were requested by the GDG: 1. Age: children (≤ 19 years) versus adults (20–60 years) versus older adults (≥ 60 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Time from symptom onset. 4. Serological status (seropositive versus seronegative). 5. Vaccination status (unvaccinated versus vaccinated). Studies did not enrol children, nor patients with severe or critical illness. All studies enrolled unvaccinated individuals with time from symptom onset < 5 days. Data regarding serological status were not reported. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Molnupiravir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.06 (CI 95% 0 — 0.4) Based on data from 4796 participants in 6 studies. (Randomized controlled) 6 per 1000 Difference: 0 per 1000 6 fewer per 1000 ( CI 95% 6 fewer — 4 fewer ) Low Due to serious imprecision and indirectness 1 Molnupiravir may have a small effect on mortality Mechanical ventilation Odds ratio 1 (CI 95% 0.02 — 59.74) Based on data from 1220 participants in 1 study. (Randomized controlled) 8 per 1000 Difference: 8 per 1000 0 fewer per 1000 ( CI 95% 8 fewer — 317 more ) Very low Due to serious risk of bias and extremely serious imprecision 2 The effect of molnupiravir on mechanical ventilation is very uncertain Admission to hospital Risk in trials Odds ratio 0.54 (CI 95% 0.3 — 0.89) Based on data from 4688 participants in 5 studies. (Randomized controlled) 35 per 1000 Difference: 19 per 1000 16 fewer per 1000 ( CI 95% 24 fewer — 4 fewer ) Moderate Due to serious imprecision 3 Molnupiravir probably reduces hospital admission Admission to hospital Higher risk Odds ratio 0.54 (CI 95% 0.3 — 0.89) Based on data from 4688 participants in 5 studies. (Randomized controlled) 60 per 1000 Difference: 33 per 1000 27 fewer per 1000 ( CI 95% 41 fewer — 6 fewer ) Moderate Due to serious imprecision 4 Molnupiravir probably reduces hospital admission Admission to Odds ratio 0.54 (CI 95% 0.3 — 0.89) 100 57 Moderate Due to serious Molnupiravir probably reduces hospital Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 47 of 142 per 1000 per 1000 hospital Highest risk imprecision 5 admission Outcome Timeframe Study results and measurements Comparator Standard care Intervention Molnupiravir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, who are not easily identifiable. For these patients, molnupiravir may have an important impact on mortality. Imprecision: serious. There were only 11 events total (10 in the control arms and 1 in the molnupiravir arms). 2. Risk of bias: serious. The single trial reporting mechanical ventilation was not blinded. Imprecision: extremely serious. Very few events, resulted in very large credible intervals that include important and unimportant effects. 3. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 4. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 5. Imprecision: serious. The upper credible interval includes a small and unimportant effect on hospitalization (4 fewer per 1000). 6. Risk of bias: serious. All three trials were at high risk of bias for deviations from intended intervention (lack of blinding). One trial was at high risk of bias for possible inadequate randomization concealment. Based on data from 4688 participants in 5 studies. (Randomized controlled) Difference: 43 fewer per 1000 ( CI 95% 68 fewer — 10 fewer ) Adverse effects leading to drug discontinuation Based on data from 4796 participants in 6 studies. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 0 fewer — 2 more ) High There is little or no difference in adverse effects leading to drug discontinuation Time to symptom resolution Lower better Based on data from 3078 participants in 3 studies. (Randomized controlled) 9 (Median) Difference: 5.6 (Mean) MD 3.4 fewer ( CI 95% 4.8 fewer — 1.7 fewer ) Moderate Due to serious risk of bias 6 Molnupiravir probably reduces duration of symptoms Malignancy In vitro and animal studies suggest the possibility of carcinogenesis Very low No human data with long-term follow-up The effect of molnupiravir on cancer is uncertain Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 48 of 142 Mitigation strategies to address safety concerns 6.6.1 Mechanism of action Molnupiravir an orally available antiviral, which was originally designed as an influenza treatment, although not approved. The drug inhibits replication of SARS-CoV-2 with an in vitro potency broadly, similar to remdesivir, and was re-purposed early in development as an antiviral for SARS-CoV-2 (47)(48). Molnupiravir is an orally available prodrug of ß-D-N4-hydroxycytidine (NHC). It is a nucleoside drug, but the mechanism of action involves lethal mutagensis of the virus. This contrasts with chain-termination seen with other antiviral nucleoside analogues (e.g. remdesivir and those used in HIV or HCV) (49). NHC is incorporated by the SARS-CoV-2 RdRp, instead of either C or U nucleosides, into the genomic or subgenomic RNA during copying of the RNA template genome. The resultant NHC- containing RNAs are then themselves used as a template for production of subsequent RNAs which are predicted to be mutated and therefore not believed to form functional viruses (49)(50). Molnupiravir is given orally twice daily unlike remdesivir, which is given by intravenous infusion once daily. In healthy volunteers, molnupiravir (800mg) achieves maximum plasma concentrations of its active metabolite at 3600 ng/mL (51). This is higher than that of remdesivir (2200 ng/mL) (52). However, the intracellular half-life of molnupiravir active metabolite is shorter in human cell lines (3h) compared with that of remdesivir's active metabolite (35h) (51). High doses of molnupiravir (250 mg/kg twice daily) have been shown to be effective in SARS-CoV-2-infected Syrian golden hamsters; however, the animal plasma pharmacokinetics were not reported to benchmark against those seen in humans (53). Evidence of antiviral activity is also available from a study in SARS-CoV-2-infected ferrets at lower doses (54). When molnupiravir was combined with favipiravir in infected Syrian golden hamsters, the efficacy was greater than when either drug was given alone (55). Molnupiravir retains activity against Alpha and Beta variants in vivo (56), and the Delta and Omicron variants in vitro (57)(58). No data are currently available demonstrating activity against the Delta or Omicron variants in vivo, and while there appears to be no molecular basis for a loss of activity, there is residual uncertainty around whether a higher replication or transmission rate may impact efficacy of the drug. Info Box With the safety concerns related to molnupiravir (see Mechanism of action section), the WHO recognizes the need to mitigate risks, both for individual patients and at the population level. The conditional recommendation takes into account one such strategy: limiting the intervention to patients that are at higher risk of hospitalization or death. Typical characteristics of people at highest risk include those with older age, immunodeficiencies and/or chronic diseases (e.g. diabetes) and lack of COVID-19 vaccination. See WHO recommendations for further information on COVID-19 vaccination Strategic Advisory Group of Experts on Immunization for more details. Other mitigation strategies include: • Decisions around treatment with molnupiravir must be done using a shared decision-making model, ensuring the clinician is well educated on the potential benefits and harms of therapy and able to explain these to the patient in order to make well-informed decisions. See Practical information section. ◦ Molnupiravir should not be given to pregnant or breastfeeding women or to children. In case of doubt about pregnancy, a pregnancy test should be performed prior to treatment initiation. If a woman of child bearing age is considered for treatment, counselling regarding birth control during treatment and for 4 days after the last dose of molnupiravir should be facilitated. ◦ Men planning to conceive should be oriented on the potential for temporary genotoxic effect on sperm cell production, and those who are sexually active with females should be counselled to use birth control during treatment and for at least 3 months after the last dose of molnupiravir (46). ◦ The unknown long-term risk of genotoxicity is likely to be higher in younger patients as compared with older patients; thus use in younger adults who are not at high risk should be limited. • Active sequence monitoring of SARS-CoV-2 detected in clinical respiratory samples (i.e. may include polymerase and spike) should be arranged for patients receiving therapy, including higher risk individuals (immunocompromised). • Pharmacovigilance: use of molnupiravir should be accompanied by a robust, active pharmacovigilance programme. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 49 of 142 Emergence of resistance: The emergence of resistance to drugs used for other viruses is varied; with some resistance emerges readily, and with others emerging more slowly. The barrier to resistance for a given drug with a given virus is generally considered to increase with the number of mutations that are required to emerge. Insufficient data are currently available to ascertain how high the barrier of resistance is with SARS-CoV-2 for molnupiravir. Based on experiences with other nucleoside antiviral drugs (some have a high barrier to resistance and some have a low barrier to resistance), molnupiravir will place a selective pressure for viral resistance mutations within an individual, with the potential to spread at a population level. Non- clinical and/or clinical data are therefore needed, but are not currently available for molnupiravir. Resistance occurs through inherent variability in viral sequences that happen spontaneously as the virus replicates. Chance variations become selected, known as selective pressure, when they confer a survival advantage in the presence of the drug. Sometimes, there is a fitness cost to the virus and secondary mutations can subsequently be selected to restore fitness. The major uncertainty relates to how quickly resistance will emerge rather than whether it will emerge. There may be a higher risk of resistance in immunocompromised patients because of a longer tail of replication in this group. There may also be a higher risk of resistance in patients with poor adherence where the virus is exposed to suboptimal drug concentrations. The rate at which resistance emerges will be slower if drugs are given in combination because more mutations will be required to confer resistance to multiple drugs than will be required for one drug. Of note, animal studies have also demonstrated drug combinations to be more effective. The risk of resistance to individual patients is drug failure due to compromised efficacy. If resistance is transmitted, there is a risk of efficacy failure at a population level and subsequent attempts to combine the drug may be futile because of “functional monotherapy” with the partner agent. The genetic barrier to resistance cannot be estimated without data. Emergence of new variants: It has been proposed that random mutagenesis arising from the molnupiravir mechanism of action might increase diversity in the viral sequences that may result in more rapid emergence of new variants (59). Unlike in the considerations for resistance, there is no conceptual basis for molnupiravir placing a selective pressure on emergence of new variants. Sequence variation is lower given molnupiravir is only incorporated in place of two of the four nucleotide bases in the genome than it would be if incorporated in place of any nucleotide. There is no direct evidence to support or refute the variants hypothesis and as such the risk is currently unquantifiable. The rate of resistance emergence and the risk of additional diversity in the viral genome leading to new variants, were acknowledged to be higher with a higher number of patients receiving the intervention. Non-clinical safety: The GDG reviewed the publically available data on non-clinical safety of molnupiravir from the FDA meeting documents for molnupiravir Emergence Use Authorization (30 November 2021) (60). The following safety concerns were highlighted: • Genetic toxicology data demonstrated that molnupiravir is mutagenic in vitro, but there was no evidence of mutagenicity in animal models. The GDG acknowledged uncertainties in the available data and concluded that based upon the available information molnupiravir may or may not be carcinogenic in humans. • An increase in thickness of growth plate associated with decreased bone formation was observed in rapidly growing rats but not in mice, rats or dogs. The GDG determined that molnupiravir should not therefore be administered to paediatric patients. • Importantly, low concentrations of NHC (0.09% maternal exposures) were detectable in 10-day old rat pups suggesting that NHC is present in breast milk. The GDG determined molnupiravir should not be administered to breastfeeding women. • In developmental and reproductive toxicology assessments, reduced foetal body weights were observed in rats and rabbits, with higher exposures also being associated with embryo-foetal lethality and teratogenicity in rats. Accordingly, molnupiravir should not be administered during pregnancy. • There was an absence of available data relating to spermatogenesis, which may be particularly prone to the effect of a mutagen in adult males. No data are available to quantify the consequences of this for embryo/foetus conceived by fathers who were receiving or had recently received molnupiravir. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 50 of 142 Baricitinib, for patients with severe or critical COVID-19 Practical Info Additional considerations are available in a summary of practical issues. Useful information can also be found in the United States Food and Drug Administration (FDA) fact sheet for health care providers, based on the emergency use authorization (EUA) of baricitinib (61). Here follows a brief summary of key points: Route, dosage and duration: • The recommended dose is 4 mg daily orally in adults with eGFR ≥ 60 mL/min/1.73 m2. • A duration of 14 days of total treatment or until hospital discharge, whichever is first. The optimal duration of treatment is unknown, and the proposed duration reflects what was used in the trials providing evidence on treatment effects of baricitinib. Dose regimen adjustment: • Patients with leukopenia, renal impairment or hepatic impairment (note: these parameters should be monitored during treatment); • Patients taking strong organic anion transporter 3 (OAT3) inhibitors (e.g. probenecid), there are drug interactions which warrant dose reductions. Timing: Baricitinib (like IL-6 receptor blockers) should be initiated at the same time as systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. Evidence To Decision Info Box Recommendations concerning janus kinase (JAK) inhibitors, specifically baricitinib, ruxolitinib and tofacitinib, for patients with severe or critical COVID-19 were published on 14 January 2022 as the eighth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of three RCTs for baricitinib, two RCTs for ruxolitinib, and one RCT for tofacitinib, as per the LNMA on drug therapies (1). No changes were made to the JAK inhibitors recommendations in this eleventh version of the guideline; however, we are aware of recent publication of RECOVERY trial that supports our previous recommendation and are currently reviewing. Strong recommendation for We recommend treatment with baricitinib (strong recommendation for). • Along with baricitinib, corticosteroids should also be administered in patients with severe or critical COVID-19 (see Section 6.15). • IL-6 receptor blockers (tocilizumab or sarilumab) have previously been recommended for the treatment of patients with severe or critical COVID-19 (see Section 6.11). An IL-6 receptor blocker and baricitinib should not be given together, and should be viewed as alternatives. The choice of whether to use baricitinib or an IL-6 receptor blocker depends on availability, as well as clinical and contextual factors (see Justification). Benefits and harms In patients with severe or critical illness, baricitinib probably reduces mortality and duration of mechanical ventilation, and reduces hospital length of stay. It probably results in little or no increase in serious adverse events. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no evidence of a subgroup effect on relative risk in younger (< 70 years) versus older patients; those with critical versus severe Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 51 of 142 6.7 Janus kinase inhibitors (published 14 January 2022) Justification When moving from evidence to the strong recommendation to use baricitinib in patients with severe or critical COVID-19, the GDG emphasized the benefits on survival and decreased length of hospital stay with ease of administration and the likelihood of little or no serious adverse events attributable to the drug. The GDG acknowledged that some serious adverse events, such as fungal infections, may not have been accurately captured during the relatively short follow-up period in the included trials. baseline. Certainty of evidence was rated as: moderate for decreased mortality (rated down from high for a large ongoing trial that may change estimates of effect and indirectness due to the relatively short follow-up period close to 28 days possibly being insufficient to capture all relevant events); high for reduction in hospital length of stay; moderate for reduction in duration of mechanical ventilation and for little or no increase in serious adverse events, both rated down for serious imprecision; and low for need for mechanical ventilation, rated down for very serious imprecision. The GDG noted in particular that the risk of serious infections (bacterial and fungal) may vary considerably in different parts of the world according to the background prevalence of infections (such as tuberculosis). This may not be so important given the short course of baricitinib used for treatment of COVID-19, but evidence is limited given the limited geographic spread of the included trials and short follow-up periods. Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with severe or critical COVID-19 would want to receive baricitinib due to the likely reduction in mortality, and moderate certainty evidence of little or no increase in serious adverse events. The benefit of baricitinib on mortality was deemed of critical importance to patients and the GDG was reassured by the moderate certainty evidence of little or no increase in serious adverse events. The GDG anticipated little variation in values and preferences between patients for this intervention. Values and preferences Resource implications, equity and human rights Compared with some other candidate treatments for COVID-19, baricitinib is expensive. The recommendation does not take account of cost-effectiveness. Access to these drugs is challenging in many parts of the world, and, without concerted effort, is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. On 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which includes baricitinib. At a time of drug shortage, it may be necessary to prioritize use of baricitinib through clinical triage (6) such as prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course, and avoiding baricitinib in those with established multi-organ failure (in whom the benefit is likely to be smaller). Acceptability and feasibility As baricitinib is administered orally once daily, hospitalized patients should find it easy to accept this treatment. In patients who cannot swallow tablets, baricitinib can be crushed, dispersed in water, and given via a nasogastric tube (see Practical info). Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 52 of 142 COVID-19; those receiving and not receiving corticosteroids at baseline; and those receiving and not receiving remdesivir at below). Costs and access were important considerations and the GDG recognizes that this recommendation could exacerbate health inequities. This strong recommendation will provide impetus to address these concerns and maximize access across regions and countries. The GDG did not anticipate important variability in patient values and preferences, and judged that other contextual factors would not alter the recommendation (see Evidence to Decision). Emerging evidence When making the strong recommendation for treatment with baricitinib, The GDG carefully considered the implications of a yet unpublished large trial (RECOVERY) having randomized patients to baricitinib or no baricitinib. Uncertainties regarding this trial included the proportion of patients who also received an IL-6 receptor blocker (see below), and when the information will be available. The GDG considered the benefits of baricitinib, supported by moderate to high certainty evidence, sufficient for an immediate strong recommendation for use of the drug, with readiness to update the living guideline as necessary once RECOVERY trial data are published. The RECOVERY trial is now published (ref) and confirms the beneficial effects of baricitinib in patients with severe and critical COVID-19. The GDG will fully assess the updated evidence for baricitinib once the LNMA has been updated and before the next iteration of the guideline. The role of IL-6 receptor blockers and baricitinib The GDG has previously made a strong recommendation for use of IL-6 receptor blockers (tocilizumab and sarilumab) in patients with severe or critical COVID-19. The GDG carefully considered whether, on the basis of the current evidence, baricitinib should be administered as an alternative to IL-6 receptor blockers or in addition to IL-6 receptor blockers. Combining them may unacceptably increase harms, including secondary bacterial and fungal infections. In the absence of evidence of incremental benefit, the GDG advises that clinicians do not administer the drugs together. The issue then arises regarding the basis for choosing between IL-6 receptor blockers and baricitinib (see Research evidence). The drugs have not undergone direct comparisons, and so the best evidence of their relative effects comes from indirect comparisons generated by the LNMA that informs these guidelines. Baricitinib may reduce mortality relative to IL-6 receptor blockers (low certainty) and may reduce the duration of mechanical ventilation (low certainty). There may be little or no difference in the agents’ impact on mechanical ventilation (low certainty), and there is probably little or no difference in adverse events leading to discontinuation (moderate certainty) (see Summary of Findings table in Research evidence). The GDG felt that the low certainty evidence did not warrant a recommendation favouring the use of baricitinib versus IL-6 receptor blockers on the basis of their impact on patient-important benefits and harms. Therefore, when both agents are available, clinicians should choose between them based on other considerations. These might include experience and comfort using the drugs; local institutional policies; route of administration (baricitinib is oral; IL-6 receptor blockers are intravenous); and cost. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regard to administration of baricitinib to pregnant or lactating women. The decision regarding use of this therapeutic should be made between the pregnant individual and their health care provider while discussing whether the potential benefit justifies the potential risk to the mother and fetus (see Research evidence and Practical info tabs). Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Baricitinib Comparator: Standard care Summary Evidence summary The LNMA for baricitinib was informed by three RCTs which enrolled 2659 patients across disease severities (62)(63)(64). All RCTs were registered, and two were published in peer-reviewed journals (63)(64); one study was a pre-print (62). All three RCTs enrolled patients in in-patient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 53 of 142 Because of different mechanisms of action, the GDG considered baricitinib separately from other JAK inhibitors (as outlined For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of baricitinib compared with standard care for the outcomes of interest, with certainty ratings, informed by the LNMA (1). Baseline risk estimates For severe and critical illness, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence (see Section 7). Subgroup analysis Four pre-specified subgroup analyses were undertaken for JAK inhibitors as a class rather than for individual drugs: 1. Age: younger adults (< 70 years) versus older adults (≥ 70 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Concomitant use of corticosteroids at baseline. 4. Concomitant use of remdesivir at baseline. No evidence of subgroup effects was identified on the relative risk of critical outcomes across all pre-specified effect modifiers. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.62 (CI 95% 0.44 — 0.85) Based on data from 2659 participants in 3 studies. (Randomized controlled) 130 per 1000 Difference: 85 per 1000 45 fewer per 1000 ( CI 95% 68 fewer — 17 fewer ) Moderate Due to ongoing recruitment in a large RCT Baricitinib probably reduces mortality. Mechanical ventilation Odds ratio 0.8 (CI 95% 0.52 — 1.19) Based on data from 2434 participants in 2 studies. (Randomized controlled) 116 per 1000 Difference: 95 per 1000 21 fewer per 1000 ( CI 95% 52 fewer — 19 more ) Low Due to very serious imprecision 1 Baricitinib may reduce mechanical ventilation. Adverse effects leading to drug discontinuation Based on data from 1611 participants in 2 studies. (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 0 more — 28 more ) Moderate Due to serious imprecision 2 Baricitinib probably results in little or no increase in serious adverse effects. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 12.8 days (Median) Difference: 11.4 days (Mean) MD 1.4 fewer ( CI 95% 2.4 fewer — 0.4 fewer ) High Baricitinib reduces duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 54 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: very serious. Credible interval includes an important decrease and increase in mechanical ventilation. 2. Imprecision: serious. The credible interval includes an important increase in adverse effects. 3. Imprecision: serious. The credible interval includes no important difference. 4. Imprecision: very serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 14.7 days (Median) Difference: 11.5 days (Mean) MD 3.2 fewer ( CI 95% 5.9 fewer — 0.5 fewer ) Moderate Due to serious imprecision 3 Baricitinib probably reduces duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 9.9 days (Median) Difference: 8.9 days (Mean) MD 1 fewer ( CI 95% 2.9 fewer — 1.1 more ) Low Due to very serious imprecision 4 Baricitinib may reduce time to clinical stability. Clinical Question/ PICO Population: Patients with severe and critical COVID-19 Intervention: Baricitinib Comparator: Interleukin-6 receptor blockers Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.77 (CI 95% 0.53 — 1.1) Based on data from 2659 participants in 3 studies. (Randomized controlled) 118 per 1000 Difference: 96 per 1000 22 fewer per 1000 ( CI 95% 52 fewer — 9 more ) Low Due to serious imprecision and ongoing recruitment in a large RCT 1 Baricitinib may reduce mortality. Mechanical ventilation Odds ratio 1.01 (CI 95% 0.61 — 1.6) Based on data from 2434 participants in 2 studies. (Randomized controlled) 94 per 1000 Difference: 96 per 1000 2 more per 1000 ( CI 95% 38 fewer — 44 more ) Low Due to very serious imprecision 2 There may be little or no difference on mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 55 of 142 Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. The credible interval includes no important difference. 2. Risk of bias: no serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: very serious. The credible interval includes important benefit and important harm. 3. Imprecision: serious. The credible interval includes small but important harm. 4. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Inconsistency: serious. The trials that studied interleukin-6 receptor blockers had discrepant results: some increased length of stay, others reduced length of stay. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. The credible interval includes no important difference. 6. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Adverse effects leading to drug discontinuation Based on data from 2309 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 1 per 1000 1 more per 1000 ( CI 95% 11 fewer — 15 more ) Moderate Due to serious imprecision 3 There is probably little to no difference in adverse effects leading to discontinuation. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 8.1 days (Median) Difference: 11.2 days (Mean) MD 3.1 more ( CI 95% 3.8 fewer — 9.9 more ) Very low Due to serious risk of bias, serious inconsistency, and very serious imprecision 4 The impact on hospital length of stay is very uncertain. Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 13.8 days (Median) Difference: 11.6 days (Mean) MD 2.2 fewer ( CI 95% 5.3 fewer — 0.7 fewer ) Low Due to serious risk of bias and imprecision 5 Baricitinib may reduce duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 8.4 days (Median) Difference: 8.9 days (Mean) MD 0.5 more ( CI 95% 2.3 fewer — 3.2 more ) Low Due to serious risk of bias and imprecision 6 There may not be an important impact on time to clinical stability. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 56 of 142 Ruxolitinib and tofacitinib, for patients with severe or critical COVID-19 Practical Info Route, dosage and duration: We refer to the table of trial characteristics (ruxolitinib and tofacitinib) to guide the administration of these agents, in the absence of other available information. Timing: Ruxolitinib or tofacitinib (like IL-6 receptor blockers) should be initiated with systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. Evidence To Decision Conditional recommendation against We suggest not to use ruxolitinib or tofacitinib (conditional recommendation against). • Clinicians should consider using these drugs only if neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) are available. • The GDG emphasized the need for more trial evidence to better inform the recommendations. The effects of ruxolitinib or tofacitinib on mortality, need for mechanical ventilation and hospital length of stay remain uncertain. Tofacinib may increase adverse events leading to drug discontinuation. Subgroup analyses were undertaken for JAK inhibitors as a class (rather than on individual drugs) and revealed no evidence of a subgroup effect on relative risk in younger (< 70 years) versus older patients; those receiving and not receiving corticosteroids; those with severe versus critical COVID-19; and those receiving and not receiving remdesivir. Benefits and harms Due to serious imprecision due to small cohorts (ruxolitinib: two RCTs, 475 patients; tofacitinib: one RCT, 289 patients) with few events and serious indirectness (pertaining to RCTs for ruxolitinib, most patients did not receive corticosteroids), certainty of evidence was rated as low or very low for all prioritized outcomes for both drugs. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that, given the low or very low certainty evidence on mortality and the other prioritized benefit outcomes and the remaining possibility of serious adverse effects, the majority of well-informed patients would not want to receive ruxolitinib or tofacitinib. The GDG anticipated, however, that because benefit has not been excluded, and because a class effect of JAK inhibitors might exist (such that baricitinib provides indirect evidence of benefit for the other JAK inhibitors), a minority of well-informed patients would choose to receive one or other drug in circumstances in which neither baricitinib nor IL-6 receptor blockers (tocilizumab or sarilumab) were available. Values and preferences Resource implications, equity and human rights The GDG noted that, given the recommendation against use of ruxolitinib or tofacitinib, efforts to ensure access to drugs should focus on those that are currently recommended. Acceptability and feasibility As ruxolitinib and tofacitinib are administered orally twice daily, this treatment should be easy to accept for hospitalized patients with severe and critical COVID-19. In patients unable to swallow whole tablets, they can be dispersed in water to take orally or via nasogastric tube (see Practical info). Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 57 of 142 Justification When moving from evidence to the conditional recommendation not to use ruxolitinib or tofacitinib in patients with severe or critical COVID-19, the GDG emphasized the low to very low certainty evidence for mortality, duration of mechanical ventilation and possible increase in serious adverse events (particularly for tofacitinib). The GDG emphasized the need for more trial evidence to better inform the recommendations; this is anticipated through ongoing trials for these JAK inhibitors. Applicability None of the included RCTs enrolled children; therefore, the applicability of this recommendation to children remains uncertain. Uncertainty also remains with regards to the administration of ruxolitinib or toficitinib to pregnant or lactating women. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Ruxolitinib Comparator: Standard care Summary Evidence summary The LNMA on ruxolitinib was informed by two RCTs that enrolled 475 patients across non-severe, severe and critical illness subgroups (65)(66). Both RCTs were registered, one was published in a peer-reviewed journal, and one was a trial registration only. Both RCTs enrolled patients in in-patient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs. For patients with severe and critical COVID-19, the GRADE Summary of Findings tables for ruxolitinib shows the relative and absolute effects compared with usual care for the outcomes of interest, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significant relative subgroup effects were found. Please see the Summary accompanying the recommendation for baricitinib for more details. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ruxolitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.87 (CI 95% 0.27 — 2.85) Based on data from 472 participants in 2 studies. (Randomized controlled) 130 per 1000 Difference: 115 per 1000 15 fewer per 1000 ( CI 95% 91 fewer — 169 more ) Very low Due to serious indirectness and very serious imprecision 1 The effect of ruxolitinib is very uncertain. Mechanical ventilation Odds ratio 0.87 (CI 95% 0.36 — 2.04) Based on data from 472 participants in 2 studies. (Randomized controlled) 116 per 1000 Difference: 108 per 1000 8 fewer per 1000 ( CI 95% 71 fewer — 94 more ) Very low Due to serious indirectness and very serious imprecision 2 The effect of ruxolitinib is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 58 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ruxolitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit. 2. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important harm and important benefit. 3. Imprecision: very serious. There was only one event in the single trial that reported this outcome, of 424 patients enrolled in the study. 4. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Indirectness: serious. Imprecision: very serious. 6. Indirectness: serious. Most patients probably did not receive corticosteroids at baseline. Concomitant use of Adverse effects leading to drug discontinuation Based on data from 484 participants in 1 study. (Randomized controlled) 0 per 1000 Difference: 5 per 1000 2 more per 1000 ( CI 95% 0 more — 15 more ) Low Due to very serious imprecision 3 Ruxolitinib may not cause an important increase in adverse effects leading to drug discontinuation. Hospital length of stay Lower better Based on data from 472 participants in 2 studies. (Randomized controlled) 12.8 days (Median) Difference: 11.4 days (Mean) MD 0.1 more ( CI 95% 2.1 fewer — 2.4 more ) Very low Due to serious indirectness and very serious imprecision 4 The impact of ruxolitinib on hospital length of stay is very uncertain. Duration of mechanical ventilation Based on data from 3 participants in 1 study. (Randomized controlled) 14.7 days (Median) Very low Insufficient data 5 The effect of ruxolitinib on mechanical ventilation is unknown. Time to clinical stability Lower better Based on data from 472 participants in 2 studies. (Randomized controlled) 9.9 days (Median) Difference: 9.8 days (Mean) MD 0.1 fewer ( CI 95% 2.5 fewer — 2.8 more ) Very low Due to serious indirectness and very serious imprecision 6 The impact of ruxolitinib on time to clinical stability is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 59 of 142 corticosteroids potentiates the beneficial effect interleukin-6 receptor blockers. Interleukin-6 is downstream in the Janus kinase pathway. Therefore, the effect of ruxolitinib may have been larger had most patients received steroids. Further, the ruxolitinib trial probably included many patients with non-severe disease. A beneficial effect of Janus kinase inhibitors may be limited to patients with severe or critical disease. Imprecision: very serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Tofacitinib Comparator: Standard care Summary Evidence summary The LNMA for tofacitinib was informed by one RCT that enrolled 289 patients across non-severe, severe and critical illness subgroups (67). The trial was registered and published in a peer-reviewed journal; it excluded children and pregnant women. Table shows characteristics of the RCT. For patients with severe or critical COVID-19, the GRADE Summary of Findings table for tofacitinib shows the relative and absolute effects compared with standard care for the outcomes of interest, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The GDG pre-specified several subgroup analyses of interest across all JAK inhibitors of interest; of these, no significant relative subgroup effects were found. Please see the Summary accompanying the recommendation for baricitinib for more details. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Tofacitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.47 (CI 95% 0.11 — 1.63) Based on data from 289 participants in 1 study. (Randomized controlled) 130 per 1000 Difference: 78 per 1000 52 fewer per 1000 ( CI 95% 113 fewer — 69 more ) Very low Due to extremely serious imprecision 1 The effect of tofacitinib is uncertain. Mechanical ventilation Odds ratio 0.5 (CI 95% 0.17 — 1.37) Based on data from 289 participants in 1 study. (Randomized controlled) 116 per 1000 Difference: 68 per 1000 48 fewer per 1000 ( CI 95% 94 fewer — 35 more ) Very low Due to extremely serious imprecision 2 The effect of tofacitinib is uncertain. Adverse effects leading to drug discontinuation Based on data from 284 participants in 1 study. (Randomized controlled) 0 per 1000 77 per 1000 Low Due to very serious imprecision 3 Tofacitinib may increase adverse effects leading to drug discontinuation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 60 of 142 6.7.1 Mechanism of action Type I and type II cytokine receptors are a family of receptors employed by over 50 interleukins, interferons, colony stimulating factors, and hormones (68). The intracellular signalling triggered by these receptors is mediated by Janus kinases (JAKs), a small family of kinases including JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Type I cytokines include IL-2, IFN-γ, IL-12, and TNFb, and type II cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. JAK inhibitors are a class of drugs which inhibit intracellular signalling through multifactorial effects on cytokine signalling. As a consequence, they interfere with many cellular responses, including antiviral responses, angiotensin-converting enzyme 2 (ACE2) expression, T cell function and differentiation, and macrophage activation (68). Baricitinib, ruxolitinib, and tofacitinib are three of at least nine JAK inhibitors. These three drugs are all generally considered to be non-specific JAK inhibitors, but differences in the specificity and potency for different JAKs are evident. Baricitinib has been described as a JAK1/JAK2 inhibitor, ruxolitinib as JAK1/JAK2 > TYK2, and tofacitinib as JAK3/JAK1 > JAK2/TYK2; other differences have also been previously described (68)(69)(70). Studies evaluating JAK inhibitors for the treatment of COVID-19 have been conducted at doses that are as high or higher than those approved for other indications, such as rheumatoid arthritis, myelofibrosis, and ulcerative colitis. Therefore, plausibility is contingent upon the role of cytokine signalling in COVID-19, and not on whether the pharmacokinetics at the studied dose is Outcome Timeframe Study results and measurements Comparator Standard care Intervention Tofacitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: extremely serious. The credible interval includes important benefit and important harm. There were only 12 events total. 2. Imprecision: extremely serious. Credible interval includes important benefit and important harm. There were only 18 events in total. 3. Imprecision: very serious. Very few events: only 21 in total (16/142 in tofacitinib arm and 5/142 in placebo arm). 4. Imprecision: very serious. Credible interval includes no important difference. ( CI 95% 17 more — 138 more ) Hospital length of stay Lower better Based on data from 289 participants in 1 study. (Randomized controlled) 12.8 days (Median) Difference: 11.7 days (Mean) MD 1.1 fewer ( CI 95% 2.8 fewer — 0.6 more ) Low Due to very serious imprecision 4 Tofacitinib may reduce duration of hospitalization. Duration of mechanical ventilation 14.7 days (Median) Very low No data The impact of tofacitinib on duration of mechanical ventilation is unknown. Time to clinical stability 9.9 days (Median) Very low No data The effect of tofacitinib on time to clinical stability is unknown. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 61 of 142 Difference: 77 more per 1000 sufficient to inhibit the target proteins. There are notable differences in the approved doses, schedules, pharmacokinetics, contraindications, and indications of these drugs for other indications. Collectively, these differences limit the confidence to consider a class-wide recommendation with currently available data. 6.8 Sotrovimab (published 14 January 2022) For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Route, dosage and duration: Additional considerations are available in a summary of practical issues. Here follows a brief summary of key points. • The authorized dose for sotrovimab is one single intravenous infusion of 500 mg over 30 minutes, administered as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset. • Sotrovimab is available as a concentrated solution, and must be diluted prior to administration. • Patients should be clinically monitored patients during the infusion, and observed for at least 1 hour after the infusion is completed. Evidence To Decision Info Box Recommendations concerning sotrovimab for patients with non-severe COVID-19 were published on 14 January 2022 as the eighth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of one RCT for non-severe illness, as per the LNMA on antibody and cellular therapies (2). No changes were made to the sotrovimab recommendation in this eleventh version of the guideline. The GDG is currently assessing to what extent the increasingly predominant Omicron BA.2 variant is substantially reducing the clinical efficacy of sotrovimab, at this stage demonstrated through pre-clinical in-vitro data (see Mechanism of action). The GDG also notes that several therapeutic alternatives are available for patients with non-severe COVID-19 at highest risk of hospitalization (see Section 6.1 and remarks below the recommendation). Conditional recommendation for We suggest treatment with sotrovimab (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk of being hospitalized. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies, including sotrovimab and casirivimab-imdevimab. • The GDG concluded that nirmatrelvir-ritonavir may represent a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. • The Omicron BA.2 variant may substantially reduce clinical efficacy of sotrovimab; the GDG is currently assessing this issue. • Patients with severe or critical COVID-19: based on current evidence, the benefit of sotrovimab in seronegative patients with severe or critical COVID-19 (see casirivimab-imdevimab recommendation in Section 6.10) remains unclear. This means that careful clinical judgment needs to be applied if casirivimab-imdevimab is unavailable and sotrovimab is considered. Benefits and harms In patients with non-severe illness, sotrovimab probably reduces hospitalization, with little or no impact on infusion reactions, with no data on time to clinical improvement. Sotrovimab probably has little or no impact on mortality and on mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 62 of 142 Justification A combination of the evidence, values and preferences, and feasibility contributed to the conditional recommendation for the use of sotrovimab only in individuals with non-severe COVID-19 at highest risk of hospitalization. Typical characteristics of people at highest risk include those who are unvaccinated, older people, or those with immunodeficiencies and/or chronic investigators. The evidence summary was informed by one RCT with 1057 patients (COMET-ICE), included in the LNMA (74). This trial provides evidence of moderate certainty for reduced hospitalization (due to serious imprecision), high certainty for absence of infusion reactions, moderate certainty (due to serious indirectness) for no or small difference in mortality and low certainty (due to serious indirectness and imprecision) for no or small difference in mechanical ventilation. Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represent the major source of indirectness for which the GDG rated down the certainty of the evidence. In addition, the GDG felt that there was some indirectness because of the possible emergence of variants for which the effectiveness of currently available monoclonal antibodies may be reduced. When rating precision, the GDG considered the estimates of the absolute risks. Accordingly, in the context of very low event rates (e.g. very low risk of death among patients with non-severe illness), the GDG did not rate down for imprecision despite relative risks with wide confidence intervals. Certainty of the Evidence Applying the agreed upon values and preferences (see Section 7), the GDG inferred that almost all well-informed patients with a low risk of hospitalization would decline sotrovimab, and only those at highest risk (e.g. unvaccinated, older, or immunosuppressed) would choose to receive treatment. In the absence of research evidence, in a previous survey (see recommendation for casirivimab-imdevimab), the GDG expressed the view that most patients with a risk of hospitalization above 10%, and thus an absolute risk reduction of approximately 6%, would choose to receive treatment, whereas most of those below that risk level would decline treatment. These thresholds were also used here. Values and preferences Acceptability and feasibility The GDG noted that sotrovimab is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This further supports the guidance that sotrovimab be reserved for those at highest risk of hospitalization. Additional challenges include the requirement for intravenous administration to patients who would normally be treated at home. Specialized clinics may be required to ensure safe and effective administration of sotrovimab. For the intervention to achieve substantial use, healthcare systems will have to address these challenges. Given the cost and availability of sotrovimab, and the obstacles to ensuring access in LMICs may prove formidable. For example, those with socioeconomic disadvantages tend to have less frequent access to services in the first 5 days of symptoms and then less access to the interventions. Thus, the panel’s suggestion that patients at highest risk receive the intervention may exacerbate health inequity. On the other hand, given the demonstrated benefits for patients and the still low vaccine coverage in some LMICs and low-income countries (LICs), sotrovimab may be a useful tool to reduce hospitalization from COVID-19 in unvaccinated populations. The recommendations should also provide a stimulus to engage all possible mechanisms to improve global access to the intervention. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. On 17 December 2021, WHO published the 7th Invitation to Manufacturers of therapeutics against COVID-19 to submit an Expression of Interest (EOI) for Product Evaluation to the WHO Prequalification Unit, which includes sotrovimab. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 63 of 142 The planned subgroup analyses could not be performed in the absence of subgroup data reported publicly or provided by diseases (e.g. diabetes). Although there is moderate certainty evidence of a substantial relative risk reduction in hospitalization, only a minority of patients who are at highest risk are likely to achieve sufficient benefit to compensate for the risks, and other limitations and disadvantages of this therapy. These include a lack of reliable tools to identify high-risk patients, delivering a parenteral therapy to patients who are typically cared for in the community, and limited availability of the drug. The role of sotrovimab and casirivimab-imdevimab Another combination of monoclonal antibodies, casirivimab-imdevimab, is also conditionally recommended in patients with non-severe COVID-19 at highest risk of hospitalization. The GDG advised that clinicians do not administer the drugs together, given an absence of evidence of incremental benefit of the drugs when given together, and the low likelihood of incremental benefit mechanistically. The GDG then considered how to choose between the two drugs. No trials provide head-to-head comparisons. With Alpha and Delta variants, there may be little or no difference in the agents’ impact on critical outcomes, according to an indirect comparison from the LNMA (see GRADE Summary of Findings table in Research evidence). Now and in the future, the choice of monoclonal antibodies will depend on emerging information regarding effectiveness with different variants and their availability, as well as clinical and contextual factors. Of note, the RCTs included in the LNMA were conducted before the emergence of the Omicron variant. Following the publication of a previous conditional recommendation for casirivimab-imdevimab, pre-clinical evidence has emerged suggesting that this monoclonal antibody combination lacks neutralization activity against the Omicron variant in vitro (71). Recent pre-clinical data demonstrate that sotrovimab has greatly reduced neutralization activity against the increasingly predominant Omicron BA.2 variant (see Mechanism of action). In the absence of clinical evidence, the effects on the efficacy of sotrovimab remains unclear and is currently being assessed by the GDG. Applicability Children and pregnant women: The included RCT enrolled only non-pregnant adults; therefore, the applicability to children and pregnant women remains uncertain. The GDG had no reason to believe that children or pregnant women with COVID-19 would respond differently to treatment with sotrovimab. However, for children, as the risk of hospitalization is generally extremely low, the GDG inferred that, in the absence of immunosuppression or another significant risk factor, children should not receive the intervention. Severe and critical COVID-19: An RCT randomized 546 adults hospitalized with COVID-19 to two neutralizing monoclonal antibody therapies (sotrovimab and BRII-196 plus BRII-198) or placebo (73). The results did not demonstrate benefits from these antibodies therapies, including a subgroup analysis on patients with seropositive versus seronegative status.Although the role of sotrovimab in severe and critical COVID-19 is not supported by the new trial, it was not assessed by the GDG, as they focused on patients with non-severe COVID-19 where evidence was available at the time of recommendation development; this trial, and any other new evidence that is publicly available, will be fully considered by the GDG for future recommendations for sotrovimab. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Sotrovimab Comparator: Standard care Summary The LNMA for sotrovimab was informed by one RCT (COMET-ICE) that randomized 1057 non-hospitalized patients with symptomatic COVID-19 (≤ 5 days after the onset of symptoms) and at least one risk factor for disease progression. Of the 1057 randomized patients, the LNMA team had access to data for 1044 patients. Included patients were randomized to receive a single infusion of sotrovimab at a dose of 500 mg, or placebo. Median age of patients was 53 years; 46% were male. Median duration of follow-up in the intention-to-treat population was 72 days. Vaccinated patients were excluded from the trial (74). The GRADE Summary of Findings table shows the relative and absolute effects of sotrovimab compared with standard care (placebo) for the outcomes of interest, with certainty ratings. Subgroup analysis Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 64 of 142 Four pre-specified subgroup analyses were requested by the GDG: 1. Age: children versus adults (< 70 years) versus older adults (≥ 70 years). 2. Severity of illness at time of treatment initiation: non-severe versus severe versus critical. 3. Time of symptom onset. 4. Serological status. No data were available in the trial to conduct these analyses. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.11 (CI 95% 0 — 2.6) Based on data from 1044 participants in 1 study. (Randomized controlled) 6 per 1000 Difference: 1 per 1000 5 fewer per 1000 ( CI 95% 6 fewer — 9 more ) Moderate Due to serious indirectness and some concerns with imprecision 1 Sotrovimab probably has little or no impact on mortality. Mechanical ventilation Odds ratio 0.11 (CI 95% 0 — 2.6) Based on data from 1044 participants in 1 study. (Randomized controlled) 8 per 1000 Difference: 1 per 1000 7 fewer per 1000 ( CI 95% 8 fewer — 13 more ) Low Due to serious indirectness and serious imprecision 2 Sotrovimab may have little or no impact on mechanical ventilation. Admission to hospital Risk in trials Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 35 per 1000 Difference: 7 per 1000 28 fewer per 1000 ( CI 95% 33 fewer — 17 fewer ) Moderate Due to serious imprecision 3 Sotrovimab probably reduces admission to hospital. Admission to hospital Higher risk Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 60 per 1000 Difference: 12 per 1000 48 fewer per 1000 ( CI 95% 56 fewer — 28 fewer ) Moderate Due to serious imprecision 4 Sotrovimab probably reduces admission to hospital. Admission to hospital Highest risk Odds ratio 0.19 (CI 95% 0.06 — 0.51) Based on data from 1044 participants in 1 study. (Randomized controlled) 100 per 1000 Difference: 21 per 1000 79 fewer per 1000 ( CI 95% 93 fewer — 46 fewer ) Moderate Due to serious imprecision 5 Sotrovimab probably reduces admission to hospital. Infusion reactions Based on data from 1044 participants in 1 0 per 1000 0 per 1000 High Sotrovimab results in little or no increase in infusion reactions. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 65 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, sotrovimab may have an important impact on mortality. Imprecision: no serious. There were only four deaths (all in the placebo group) in the single trial that studied sotrovimab. 2. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, sotrovimab may have an important impact on mechanical ventilation. Imprecision: serious. Very few events – only four patients received invasive mechanical ventilation in the single trial (all in the placebo group). 3. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. 4. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. 5. Imprecision: serious. Few events (25 total: 4 in the sotrovimab group and 21 in the placebo group); does not meet optimal information size. studies. (Randomized controlled) Difference: 0 fewer per 1000 ( CI 95% 13 fewer — 13 more ) Time to symptom resolution No data The effect of sotrovimab is unknown. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Sotrovimab Comparator: Casirivimab-imdevimab Outcome Timeframe Study results and measurements Comparator Casirivimab- imdevimab Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation Odds ratio 0 (CI 95% 0 — 0.01) (Randomized controlled) 2 per 1000 Difference: 0 per 1000 2 fewer per 1000 ( CI 95% 2 fewer — 2 fewer ) Moderate Due to serious indirectness and some concerns with imprecision 1 There is probably little or no difference on mechanical ventilation. Mortality Odds ratio 0.53 (CI 95% 0.09 — 2.12) (Randomized controlled) 3 per 1000 2 per 1000 Moderate Due to serious indirectness and some concerns with imprecision 2 There is probably little or no difference on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 66 of 142 Outcome Timeframe Study results and measurements Comparator Casirivimab- imdevimab Intervention Sotrovimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mechanical ventilation will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, whether there is an important difference in mechanical ventilation is uncertain. Imprecision: no serious. Very few events – only two patients received invasive mechanical ventilation in the single trial (both in the placebo group). 2. Indirectness: serious. The baseline risk across the entire population is very low, meaning that any impact on mortality will be very small. There are some people with much higher baseline risk, which are not easily identifiable. For these patients, the effect on mortality is uncertain. Imprecision: no serious. There was only one death (in the placebo group) in the single trial that studied sotrovimab. 3. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. 4. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. 5. Indirectness: serious. Patients at high risk are not easily identified. Imprecision: no serious. ( CI 95% 3 fewer — 3 more ) Admission to hospital Higher risk Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 18 per 1000 Difference: 12 per 1000 6 fewer per 1000 ( CI 95% 14 fewer — 17 more ) Moderate Due to serious indirectness and some concerns with imprecision 3 There is probably little or no difference in hospitalization. Infusion reactions 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 13 fewer — 13 more ) High There is little or no difference in infusion reactions. Admission to hospital Highest risk Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 31 per 1000 Difference: 21 per 1000 10 fewer per 1000 ( CI 95% 24 fewer — 28 more ) Moderate Due to serious indirectness and some concerns with imprecision 4 There is probably little or no difference in hospitalization. Admission to hospital Risk in trials Odds ratio 0.68 (CI 95% 0.21 — 1.97) (Randomized controlled) 10 per 1000 Difference: 7 per 1000 3 fewer per 1000 ( CI 95% 8 fewer — 10 more ) Moderate Due to serious indirectness and some concerns with imprecision 5 There is probably little or no difference in hospitalization. Time to clinical improvement No data The effect of sotrovimab is unknown. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 67 of 142 Difference: 1 fewer per 1000 6.8.1 Mechanism of action Sotrovimab (VIR-7831; GSK4182136) is a single human monoclonal antibody that binds to a conserved epitope of the SARS- CoV-2 spike protein, preventing the virus from entering cells. Sotrovimab is an Fc-engineered IgG monoclonal antibody that is expected to have a longer half-life than unmodified IgG monoclonal antibodies, but there are no publicly available data regarding its half-life in humans. No published pre-clinical or human pharmacokinetic data were available for review; assessment was therefore based upon public regulatory information and the GSK Product Monograph (75). Antiviral activity in a Syrian Golden hamster model of SARS-CoV-2 infection was demonstrated at 5 mg/kg IP but with a version of the antibody that was not Fc-engineered (75). Neutralization of SARS-CoV-2 (USA WA1/2020) was achieved in Vero E6 cells with an EC90 value of 0.19 µg/mL (76). Sotrovimab serum concentrations in COMET-ICE (single 500 mg IV infusion) provided geometric mean Cmax (at the end of a 1 hr IV infusion) of 117.6 µg/mL (N=129, CV% 40) and a geometric mean Day 29 serum concentration of 24.5 µg/mL (76). Population mean serum concentrations are therefore expected to be 129-fold higher after 29 days than the concentrations needed in vitro to neutralize the original strain of SARS-CoV-2. A review manuscript with Vir Biotechnology authors indicates less than 10-fold loss of neutralization for sotrovimab for all tested variants of concern, which did not at the time include Omicron (77). Information in the FDA Emergency Use Authorization also state “no change” in activity of sotrovimab against Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta (including with K417N), Lambda and Mu in pseudo-typed virus-like particle neutralization assays (76). Sotrovimab has been reported to retain activity against BA.1 Omicron in pseudovirus assays but with higher concentrations being required for neutralization compared with the wild-type virus (72). Several reports have indicated that the neutralization of the BA.2 sub-lineage of Omicron is more severely impacted than it is for BA.1 (79)(78)(https://www.biorxiv.org/ content/10.1101/2021.03.09.434607v10). A better understanding of the pharmacokinetic-pharmacodynamic relationship will be need to ascertain the consequences of these reduced activities for efficacy of sotrovimab. An E340A amino acid substitution in the conserved epitope of the spike protein emerged rapidly under a selective pressure with sotrovimab in cell culture, and subsequent characterization using a pseudovirus assay resulted in a > 100-fold reduction in susceptibility to sotrovimab (76). Sixteen other substitutions introduced into the epitope were also described as reducing neutralization by sotrovimab by between 5.4 and > 297-fold (76). Therefore, resistance to sotrovimab can emerge under experimental conditions. Additionally, 4 of the first 1000 consecutive patients treated with sotrovimab during a Delta wave in Australia are reported to have developed E340 mutations in their viral sequences, and remained culture positive for 12–24 days after dosing (80). 6.9 Convalescent plasma (published 7 December 2021) For patients with non-severe COVID-19 Practical Info The GDG made a strong recommendation against using convalescent plasma for the treatment of patients with non-severe COVID-19 and a recommendation against using convalescent plasma in those with severe or critical COVID-19 outside the context of a clinical trial. Given this, we will not go into detail regarding the many practical issues related to convalescent plasma Info Box Recommendations concerning convalescent plasma for patients with non-severe, severe and critical COVID-19 were published on 7 December 2021 as the seventh version of the WHO living guideline and in the BMJ as Rapid Recommendations. It follows the availability of 16 RCTs across disease severities, as per the LNMA on antibody and cellular therapies (2). No changes were made to the convalescent plasma recommendations in this eleventh version of the guideline. Strong recommendation against We recommend against treatment with convalescent plasma (strong recommendation against). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 68 of 142 including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution of plasma, and infusion of convalescent plasma into recipients. Evidence To Decision Justification A combination of the evidence, values and preferences, and feasibility contributed to the strong recommendation against convalescent plasma in patients with non-severe COVID-19. Most importantly, given there was no benefit demonstrated in any of the critical or important outcomes for either non-severe or severe or critical COVID-19, the GDG did not see any justification for the resources (including time and cost) that would be associated with administration of convalescent plasma. The recommendation also took into account possible associated harms (although not demonstrated in the evidence summary, there is always a potential for harms with blood product transfusion), the low baseline risk of mortality, mechanical ventilation, and hospitalization in non-severe illness, and feasibility challenges with the administration of convalescent plasma. Titres Titres of neutralizing antibodies varied substantially between included trials, with over half of the trials not reporting or considering recipient titres at all. In fact, the largest trial (RECOVERY) did not report on donor antibody titres at all. Even when titres were reported, the method for testing and the volume of plasma infused varied. This made it impossible to provide any analysis based on donor titre levels or assess for credible subgroup effects. In non-severe patients, convalescent plasma does not result in an important impact on mortality. Convalescent plasma probably does not impact mechanical ventilation. There were no data evaluating the risk of hospitalization with convalescent plasma and therefore the impact is very uncertain. Convalescent plasma probably does not result in important increases in risks of transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), or allergic reactions. Benefits and harms The certainty in mortality was high, whereas mechanical ventilation was moderate due to serious risk of bias. Certainty was rated as moderate for TRALI and TACO due to serious risk of bias, and for allergic reactions due to concerns regarding risk of bias and imprecision. Certainty of the Evidence The GDG inferred that, in addition to the agreed upon values and preferences (see Section 7), almost all well-informed patients would choose against receiving convalescent plasma based on available evidence regarding relative benefits and harms. From a population perspective, feasibility, acceptability, equity and cost are other important elements to take into account (see Section 7). For patients with non-severe illness, the GDG considered that resource and feasibility issues may be amplified in the outpatient setting, and mobilizing the use of convalescent plasma on a large scale would likely be of questionable feasibility. Values and preferences Acceptability and feasibility The GDG noted that convalescent plasma use is associated with significant resource requirements including identification of potential donors, testing of donors to ensure adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of plasma, transportation of plasma to recipient location, and administration of plasma. These resources and feasibility issues are compounded for those with non-severe disease who are most often outpatients. Also, this process is costly and time-consuming. Given the number of patients with non-severe disease and the low event rate in this subgroup of patients, mobilizing the use of convalescent plasma on a large scale would be of questionable feasibility. Although blood transfusion is acceptable to most, there is a subset of the population that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions related to blood product transfusion. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 69 of 142 Applicability The applicability of this recommendation to children or pregnant women is currently uncertain, as the included RCTs enrolled non-pregnant adults. The GDG had no reason to think that children with COVID-19 would respond any differently to treatment with convalescent plasma. However, the risk of hospitalization in children is generally extremely low and the GDG inferred that in the absence of immunosuppression or another significant risk factor children should not receive the intervention. Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Convalescent plasma Comparator: Standard care Summary Evidence summary The LNMA on convalescent plasma included 16 RCTs that enrolled 16 236 patients across non-severe, severe, and critical illness subgroups. All RCTs were registered, and 80% were published in peer-reviewed journals; 20% were pre- prints. 99% of participants were enrolled from in-patient settings; of them, 15% were admitted to the intensive care unit (ICU). 1% of patients were enrolled from outpatient settings. None of the included studies enrolled children or pregnant women. The Table shows characteristics of the RCTs, of which two trials used comparisons to plasma as placebo and were not included in the evidence summaries. We are aware of two additional published RCTs comparing convalescent plasma to standard care or placebo (81)(82). These trials were not incorporated in the latest analysis presented to the GDG, based on which recommendations were made. For patients with non-severe COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of convalescent plasma compared with usual care for the outcomes of interest,with certainty ratings. This evidence summary was informed by the LNMA (2) pooling data from 1602 patients in 4 RCTs for the outcome of mortality and less data available for other outcomes, except for allergic reactions (8 RCTs, 243 patients). See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis We pre-specified the following subgroup analyses of interest: 1. Age: younger adults (< 70 years) versus older adults (> 70 years). 2. Severity of illness (at time of treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma. The subgroup analyses were performed on patients across all disease severities. The majority of subgroups did not have sufficient data across outcomes of interest to pursue subgroup analyses. Of those that did, we found no significant subgroup effects for severity of illness (p=0.80) and age (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical ventilation. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mortality closest to 90 days Odds ratio 0.83 (CI 95% 0.43 — 1.46) Based on data from 1602 participants in 4 studies. 1 (Randomized controlled) 3 per 1000 Difference: 2 per 1000 1 fewer per 1000 ( CI 95% 2 fewer — 1 more ) High 2 Convalescent plasma does not result in an important impact on mortality. Mechanical ventilation closest to 90 days Odds ratio 0.71 (CI 95% 0.18 — 1.77) Based on data from 705 6 per 1000 4 per 1000 Moderate Due to serious risk of bias 4 Convalescent plasma probably does not impact mechanical Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 70 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [87], [83], [84], [86], 2. Risk of bias: no serious. The GDG did not rate down for risk of bias due to lack of blinding. . 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [83], [84], [87], 4. Risk of bias: serious. Imprecision: no serious. The GDG did not rate down for imprecision, because the credible interval excludes an important benefit and important harm. 5. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [88], [84], [89], [85], 6. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect and baseline risk is very low. 7. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], [85], [83], [88], 8. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is very low. 9. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [92], [88], [86], [83], [91], [85], [89], [90], 10. Risk of bias: serious. 2 trials (491 patients; 3% of total) were at low risk of bias vs. 6 trials (14 910 patients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some concern regarding allergic reactions, though acknowledges that the baseline risk is low. participants in 3 studies. 3 (Randomized controlled) Difference: 2 fewer per 1000 ( CI 95% 5 fewer — 5 more ) ventilation. Transfusion- related acute lung injury (TRALI) within 28 days Based on data from 1365 participants in 4 studies. 5 (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 5 fewer — 6 more ) Moderate Due to serious risk of bias 6 Convalescent plasma probably does not result in an important increase in TRALI. Transfusion- associated circulatory overload (TACO) within 28 days Based on data from 1442 participants in 4 studies. 7 (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 3 fewer — 12 more ) Moderate Due to serious risk of bias 8 Convalescent plasma probably does not result in an important increase in TACO. Allergic reactions within 28 days Odds ratio 3.25 (CI 95% 1.27 — 9.3) Based on data from 15 243 participants in 8 studies. 9 (Randomized controlled) 3 per 1000 Difference: 10 per 1000 7 more per 1000 ( CI 95% 1 more — 24 more ) Low Due to concerns with risk of bias and imprecision 10 Convalescent plasma probably does not result in an important increase in allergic reactions. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 71 of 142 For patients with severe or critical COVID-19 Practical Info The GDG made a recommendation against using convalescent plasma in those with severe or critical COVID-19 outside the context of a clinical trial and a strong recommendation against using convalescent plasma for treatment of patients with non- severe COVID-19. Given this, we will not go into detail regarding the many practical issues related to convalescent plasma including but not limited to: identification and recruitment of potential donors, collection of plasma, storage and distribution of plasma, and infusion of convalescent plasma into recipients. Evidence To Decision Justification After substantial discussion, the GDG decided to make a recommendation against convalescent plasma in patients with severe or critical COVID-19, except in the context of clinical trials. Given the low certainty evidence suggesting a small or no effect on Only in research settings We recommend not to use convalescent plasma for treatment of COVID-19, except in the context of a clinical trial (recommended only in research settings). In severe or critical patients, convalescent plasma may not result in an important impact on mortality, mechanical ventilation, time to symptom improvement, length of hospital stay or ventilator-free days. Convalescent plasma probably does not result in important increases in risks of TRALI, TACO or allergic reactions. However, there is always potential for harms with blood product transfusion although not demonstrated in the evidence summary. Benefits and harms The certainty in mortality was low due to concerns with indirectness, risk of bias and imprecision. The GDG rated down certainty to low for mechanical ventilation, length of hospital stay and ventilator-free days for serious risk of bias and serious imprecision, and to low for time to symptom improvement due to very serious imprecision. Certainty was rated as moderate for TRALI and TACO due to serious risk of bias, and for allergic reactions due to concerns regarding risk of bias and imprecision. Certainty of the Evidence The GDG inferred that, in addition to the agreed upon values and preferences (see Section 7), almost all well-informed patients would choose against receiving convalescent plasma based on available evidence regarding relative benefits and harms. From a population perspective, feasibility, acceptability, equity and cost are other important elements to take into account (see Section 7). Values and preferences Acceptability and feasibility The GDG noted that convalescent plasma use is associated with significant resource requirements including identification of potential donors, testing of donors to ensure adequate titres of anti-SARS-CoV-2 antibodies, collection of donor plasma, storage of plasma, transportation of plasma to recipient location, and administration of plasma. Also, this process is costly and time-consuming. Although blood transfusion is acceptable to most, there is a subset of the population that will not accept allogenic blood transfusion. There are also regulatory challenges in most jurisdictions related to blood product transfusion. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 72 of 142 mortality, mechanical ventilation, and time to symptom improvement, with possible associate harms (although not demonstrated in the evidence summary, there is always a potential for harms with blood product transfusion) the panel agreed further research addressing these patient-important outcomes would be valuable. This research focus on severe or critical COVID-19 was also informed by the feasibility (patients are already hospitalized) and baseline risk of mortality and requiring life support interventions (higher in severe or critical COVID-19). The panel identified high titre products as the highest priority for future research as well as the need of reporting on donor titre and volume infused which can give an idea of dilution of titres in the recipient. Similarly, the panel identified seronegative COVID-19 patients as the highest priority for future convalescent plasma research. A recommendation to only use a drug in the setting of clinical trials is appropriate when there is low certainty evidence, and future research has a potential for reducing uncertainty about the effects of the intervention and for doing so at a reasonable cost. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Convalescent plasma Comparator: Standard care Summary Evidence summary for convalescent plasma Please see summary for patients with non-severe COVID-19 above. It provides details about the LNMA and 16 included trials across disease severities, as well as subgroup analyses that did not detect credible effects based on age, severity of illness, or dosage of convalescent plasma. The GRADE Summary of Findings table shows the relative and absolute effects of convalescent plasma compared with usual care for the outcomes of interest for patients with severe and critical COVID-19, with certainty ratings. This evidence summary was informed by the LNMA (2), pooling data from from 14 366 patients in 10 studies for the outcome of mortality, with less data available for other outcomes. Baseline risk estimates For severe and critical illness, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence (see Section 7). Subgroup analysis We pre-specified the following subgroup analyses of interest: 1. Age: younger adults (< 70 years) versus older adults (> 70 years). 2. Severity of illness (at time of treatment initiation): non-severe versus severe and critical. 3. Treatment dose: higher titre versus lower titre plasma. The majority of subgroups did not have sufficient data across outcomes of interest to pursue subgroup analyses. Of those that did, we found no significant subgroup effects for severity of illness (p=0.80) and age (p=0.84) on mortality, and of severity of illness (p=0.17) on mechanical ventilation. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mortality closest to 90 days Odds ratio 0.92 (CI 95% 0.7 — 1.12) Based on data from 14 366 participants in 10 studies. 1 (Randomized controlled) 130 per 1000 Difference: 121 per 1000 9 fewer per 1000 ( CI 95% 35 fewer Very low Due to concerns with indirectness, risk of bias, and imprecision 2 Convalescent plasma may have a small or no effect on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 73 of 142 — 13 more ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation closest to 90 days Odds ratio 0.92 (CI 95% 0.46 — 1.68) Based on data from 623 participants in 5 studies. 3 (Randomized controlled) 86 per 1000 Difference: 80 per 1000 6 fewer per 1000 ( CI 95% 45 fewer — 50 more ) Low Due to serious risk of bias and serious imprecision 4 Convalescent plasma may not impact mechanical ventilation. Transfusion- related acute lung injury (TRALI) within 28 days Based on data from 1365 participants in 4 studies. 5 (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 ( CI 95% 5 fewer — 6 more ) Moderate Due to serious risk of bias 6 Convalescent plasma probably does not result in an important increase in TRALI. Transfusion- associated circulatory overload (TACO) within 28 days Based on data from 1442 participants in 4 studies. 7 (Randomized controlled) 0 per 1000 Difference: 5 per 1000 5 more per 1000 ( CI 95% 3 fewer — 12 more ) Moderate Due to serious risk of bias 8 Convalescent plasma probably does not result in an important increase in TACO. Allergic reactions within 28 days Odds ratio 3.25 (CI 95% 1.27 — 9.3) Based on data from 15 243 participants in 8 studies. 9 (Randomized controlled) 3 per 1000 Difference: 10 per 1000 7 more per 1000 ( CI 95% 1 more — 24 more ) Low Due to concerns with risk of bias and imprecision 10 Convalescent plasma probably does not result in an important increase in allergic reactions. Time to symptom improvement Lower better Based on data from 472 participants in 3 studies. 11 (Randomized controlled) 15 (Mean) Difference: 15 (Mean) MD 0 fewer ( CI 95% 10.4 fewer — 33.6 more ) Low Due to very serious imprecision 12 Convalescent plasma may not impact time to symptom improvement. Length of hospital stay Measured by: days Lower better Based on data from 1015 participants in 7 studies. 13 (Randomized controlled) 11.7 days (Mean) Difference: 11 days (Mean) MD 0.7 fewer ( CI 95% 2.3 fewer — 1 more ) Low Due to serious risk of bias and serious imprecision 14 Convalescent plasma may not impact length of hospital stay. Ventilator-free days Measured by: days High better 13.7 days (Mean) 13 days (Mean) Low Due to serious Convalescent plasma may not impact the Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 74 of 142 within 28 days 6.9.1 Mechanism of action The proposed primary mechanism of action for convalescent plasma involves the transfer of endogenously produced neutralizing antibodies present within the plasma from previously infected and recovered patients into patients with active infection (97). Therefore, the underlying plausibility for this mechanism of action depends upon whether sufficient antibody concentrations remain following the dilution from donor to recipient. As such, the neutralizing antibody titre within the donor plasma as well as the volume administered are likely to be important. Data generated in Syrian golden hamsters have demonstrated efficacy of convalescent plasma against SARS-CoV-2 at a titre of 1:2560, but not at a titre of 1:320, when given at a volume of 1 mL, which extrapolates based on average blood volume to a human dosing volume of 300 mL (98). At the extremes of the studies which have investigated convalescent plasma clinically and reported the dose in terms of neutralizing antibody titre and volume administered, administration of 200 mL would be expected to result in an average dilution of 25-fold whereas administration of 1000 mL would be expected to result in an average dilution of 5-fold from those Outcome Timeframe Study results and measurements Comparator Standard care Intervention Convalescent plasma Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], [93], [95], [92], [90], [88], [94], [86], [96], [91], 2. Risk of bias: serious. Indirectness: serious. Imprecision: serious. Credible intervals include both important benefit and important harm. 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [93], [89], [85], [92], [95], 4. Risk of bias: serious. Imprecision: serious. The GDG decided the credible intervals warranted downgrading only once for imprecision. 5. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [85], [89], [84], [88], 6. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is low. 7. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [88], [83], [89], [85], 8. Risk of bias: serious. Most patients were enrolled in unblinded studies. Imprecision: no serious. GDG decided not to rate down for imprecision, because credible interval excludes an important effect, and baseline risk is low. 9. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [91], [85], [89], [83], [92], [88], [90], [86], 10. Risk of bias: serious. 2 trials (491 patients; 3% of total) were at low risk of bias vs. 6 trials (14 910 patients) at high risk of bias. Imprecision: serious. GDG agreed the credible interval includes some concern regarding allergic reactions, though acknowledges the baseline risk is low. 11. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [89], 12. Imprecision: very serious. 13. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [93], [88], [94], [95], [96], [92], [89], 14. Risk of bias: serious. All studies except one were not adequately blinded. Imprecision: serious. Credible interval does not exclude small but important benefit. 15. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [92], [88], [90], 16. Risk of bias: serious. Almost all patients were randomized to trials that were not blinded. Imprecision: serious. Credible interval does not exclude important benefit. Based on data from 2859 participants in 3 studies. 15 (Randomized controlled) Difference: MD 0.7 fewer ( CI 95% 1.8 fewer — 0.4 more ) risk of bias and serious imprecision 16 number of ventilator- free days. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 75 of 142 titres present in the circulation of the donor themselves (assuming an average human blood volume of 5 L (99)). It should be further recognized that the concentrations (titre) of neutralizing antibodies present within convalescent plasma are highly variable between donors and that there are different methodologies available to measure it (100). Antibody titre, methodology employed, and the volume of convalescent plasma administered all vary widely across the studies that have investigated this approach in COVID-19. It should be further noted that in some trials, the antibody titre reported for eligibility was higher than the reported antibody titre in the donor plasma that was used because of the differences in methodology used for the two assessments (e.g. total IgG for donor eligibility with subsequent assessment of the specific neutralizing antibody titre (101)). There is clear uncertainty surrounding the dose of neutralizing antibodies given in different trials and this uncertainty is summarised as follows: For trials in severe/critical patients: • No cut-off in neutralizing antibody titre of the donor was applied in 9/16 studies. • Antibody titre of the donor plasma was not recorded in 12/16 trials, meaning the titre may have been high or may have been low. However, in 3 of the trials in which donor titre was not recorded, a lower cut-off was applied at a titre of either 1:160 (for 2 trials) or 1:400. • The largest trial (RECOVERY) did not report donor antibody titres although only donors with a titre above 1:100 were eligible • One (1/16) trial did not provide information on what volume of plasma was administered meaning volume could have been high or could have been low. • Both volume and donor titre were only known for 6/16 trials. Donor titres were 1:80, 1:87, 1:300, 1:320, 1:526, and 1:640 with volumes of 300, 500, 400–600, approx. 480, 750–975, and 300 mL, respectively (estimated dose range of 6-fold). For trials in non-severe patients: • Only three trials were conducted in non-severe patients using antibody titres of 1:40, 1:292, and 1:3200 with volumes administered of 250–300 mL, 400 mL and 250 mL, respectively (estimated dose range of 100-fold). • Two trials studied both non-severe and severe/critical patients, one of which didn’t record antibody titre, and the other which used 200–250 +/- 75 mL of plasma with a titre of 1:160. 6.10 Casirivimab-imdevimab (neutralizing monoclonal antibodies) (published 24 September 2021) Info Box Recommendations concerning neutralizing monoclonal antibodies (casirivimab-imdevimab) for patients with non-severe, severe or critical COVID-19 were published on 24 September 2021 as the sixth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the availability of pre-prints of four trials that were part of the larger adaptive randomized master protocol addressing patients with non-severe illness, and of the RECOVERY trial addressing severe and critically ill patients (9)(10)(11). Following the publication of a previous conditional recommendation for casirivimab-imdevimab, additional preclinical evidence has emerged (see Mechanism of action) (102). There is a substantial body of pre-clinical in vitro data, and a confirmatory in vivo evaluation, demonstrating lack of efficacy of casirivimab-imdevimab against the Omicron BA.1 variant (see Mechanism of action). As a result, casirivimab-imdevimab is no longer recommended for COVID-19 treatment except in cases where rapid viral genotyping is available and confirms infection with a SARS-CoV-2 variant (such as Delta) that is susceptible to the neutralizing activity of this combination of monoclonal antibodies. The GDG notes that several therapeutic alternatives are available for patients with non-severe COVID-19 at highest risk of hospitalization (see Section 6.1 and remarks below the recommendation). No changes were made to the convalescent plasma recommendations in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 76 of 142 For patients with non-severe COVID-19 at highest risk of hospitalization Practical Info Dosing and administration route: Intravenous total dose of the monoclonal antibody combination differed in the non-severe trials, ranging from total dose 1200 mg–8000 mg (600 mg–4000 mg each antibody), demonstrating efficacy at all doses, including the lowest tested, 1200 mg total dose (600 mg of each antibody). In the face of limited access and resource considerations, health systems will face choices concerning dose of casirivimab-imdevimab as well as intravenous or subcutaneous injections. Please see the acceptability and feasibility section (under Evidence to Decision) for some deliberations to help in making these choices within the possible range of 1200 mg–2400 mg total dose. Monitoring: Although the available trials have not convincingly shown that casirivimab-imdevimab results in allergic reactions, the possibility remains. To be administered through an intravenous line containing a sterile in-line or add-on 0.2 micron filter. Following administration, patients should undergo monitoring for severe anaphylaxis. Evidence To Decision Conditional recommendation for We suggest treatment with casirivimab-imdevimab where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e. excluding Omicron BA.1) (conditional recommendation for). • See Section 6.1 for help to identify patients at highest risk of being hospitalized. • Several therapeutic options are available: see decision support tool that displays benefits and harms of nirmatrelvir-ritonavir, molnupiravir, remdesivir and the monoclonal antibodies, including sotrovimab and casirivimab-imdevimab. • The GDG concluded that nirmatrelvir-ritonavir may represents a superior choice because it may have greater efficacy in preventing hospitalization than the alternatives, has fewer concerns with respect to harms than does molnupiravir; and is easier to administer than intravenous remdesivir and the antibodies. Updated In non-severe patients, casirivimab-imdevimab probably reduces the risk of hospitalization and duration of symptoms. Casirivimab-imdevimab is unlikely to have serious adverse effects, including allergic reactions. Benefits and harms Limitations in available empirically developed risk prediction tools for establishing patients’ risk of hospitalization represents the major source of indirectness for which the GDG rated down the certainty of the evidence (31). In addition, the GDG felt that there was some indirectness because of the possible emergence of variants in which effectiveness may be reduced. The GDG thus rated down the certainty of evidence to moderate for hospitalization and duration of symptoms. The GDG rated down evidence certainty to moderate for allergic reactions because of imprecision but considered the finding of no serious adverse effects to represent high certainty evidence. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients at typical low risk of hospitalization would decline casirivimab-imdevimab and only those at higher risk (e.g. unvaccinated, older, or immunosuppressed) would choose the treatment. Values and preferences Acceptability and feasibility Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 77 of 142 Justification A combination of the evidence, values and preferences, and feasibility contributed to the conditional recommendation for the use of casirivimab-imdevimab only in patients with non-severe COVID-19 at highest risk of hospitalization. Although there is moderate certainty evidence of a substantial relative risk reduction in hospitalization, only a minority of patients who are at highest risk are likely to achieve important benefit. In routine care of those with non-severe COVID-19, there is a lack of tools to reliably identify those at highest risk of hospitalization. This clinical complexity, combined with the limited availability of the drug and need for parenteral administration route for a group of patients who are typically cared for in the community, present a range of challenges for care that need to be addressed by health care systems. Applicability The applicability of this recommendation to children is currently uncertain, as the included RCTs enrolled adults. The GDG had no reason to think that children with COVID-19 would respond any differently to treatment with casirivimab-imdevimab. However, the risk of hospitalization in children is generally extremely low and the GDG inferred that in the absence of immunosuppression or another significant risk factor children should not receive the intervention. The GDG noted that casirivimab-imdevimab is unlikely to be available for all individuals who, given the option, would choose to receive the treatment. This further supports the guidance that casirivimab-imdevimab be reserved for those at highest risk of hospitalization. Major feasibility challenges include limited production of casirivimab-imdevimab and, for outpatients, the requirement for intravenous administration. Regarding intravenous administration, it is likely that specialized clinics with adequate amounts of the antibodies and personnel who will ensure safe and effective administration of the intervention will be required. For the intervention to achieve substantial use, health systems will have to address these challenges. Choosing a dose: Different doses of the monoclonal antibody combination were used in different trials, and health systems will face the choice of which dose to use and this can be informed by values and preferences. If one’s priority is to ensure giving as many people as possible the opportunity to benefit from treatment, one might use the lowest effective dose offered in the studies of non-severe patients, 1200 mg total dose (600 mg of each antibody) (103). If one’s priority is on ensuring effectiveness in every individual who receives treatment, and minimizing the risk of emergence of resistance, one might use a higher total intravenous dose of 2400 mg (1200 mg of each antibody). Administration route: A similar value and preference issue arises in choosing between intravenous administration – used in the four trials included in the LNMA (from a larger adaptive randomized master protocol) (104) – and subcutaneous administration, which has been used in the prophylactic trial (105). Intravenous administration will achieve maximum drug concentrations faster than subcutaneous administration; however, both will achieve exposure above the proposed therapeutic threshold. If one’s priority is to ensure maximum effectiveness in every individual who receives treatment, one might choose intravenous administration. If one’s priority is, in the face of practical difficulties of widespread intravenous administration in the community, to ensure giving as many people as possible the opportunity to benefit from treatment, one might ensure the availability of subcutaneous administration as an alternative. Volumes that can be administered subcutaneously are limited to the lowest dose, which is a total dose 1200 mg (600 mg of each antibody). Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary For patients with non-severe COVID-19, the LNMA (2) pooled data from four trials that enrolled 4722 patients randomized to casirivimab-imdevimab or usual care (104). All trials were registered and presented in pre-prints when the data were reviewed by the GDG. The Table shows trial characteristics. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 78 of 142 The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with non-severe COVID-19, with certainty ratings. Specific considerations regarding baseline risk estimates informing absolute estimates of effect For hospital admission, the key outcome driving the recommendation in favour of casirivimab-imdevimab, we used a baseline risk of 4.2% (42 in 1000) based on the median of the control arm of the four RCTs contributing to the evidence. These trials recruited patients at elevated risk of being hospitalized to increase statistical power in detecting potential treatment effects. The baseline risk is therefore appreciably higher than the risk for many patients with non-severe COVID-19. Subgroup analysis We found no evidence of subgroup effects on age or time from onset of illness in patients with non-severe COVID-19. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.57 (CI 95% 0.26 — 1.2) Based on data from 4722 participants in 4 studies. (Randomized controlled) 6 per 1000 Difference: 3 per 1000 3 fewer per 1000 ( CI 95% 4 fewer — 1 more ) Moderate Due to serious indirectness 1 Casirivimab-imdevimab do not have an important effect on mortality. Mechanical ventilation Odds ratio 0.22 (CI 95% 0.03 — 1.21) Based on data from 3432 participants in 2 studies. (Randomized controlled) 8 per 1000 Difference: 2 per 1000 6 fewer per 1000 ( CI 95% 8 fewer — 2 more ) Moderate Due to serious indirectness 2 Casirivimab-imdevimab probably do not have an important effect on mechanical ventilation. Admission to hospital Risk in trials Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 35 per 1000 Difference: 10 per 1000 25 fewer per 1000 ( CI 95% 29 fewer — 18 fewer ) Moderate Due to serious indirectness 3 Casirivimab-imdevimab probably reduce admission to hospital. Admission to hospital Higher risk Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 60 per 1000 Difference: 18 per 1000 42 fewer per 1000 ( CI 95% 49 fewer — 30 fewer ) Moderate Due to serious indirectness 4 Casirivimab-imdevimab probably reduce admission to hospital. Admission to hospital Highest risk Odds ratio 0.29 (CI 95% 0.17 — 0.48) Based on data from 4722 participants in 4 studies. (Randomized controlled) 100 per 1000 Difference: 31 per 1000 69 fewer per 1000 ( CI 95% 81 fewer Moderate Due to serious indirectness 5 Casirivimab-imdevimab probably reduce admission to hospital. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 79 of 142 — 49 fewer ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. There is substantial variability in baseline risk of death between patients. Casirivimab-imdevimab may confer an important benefit in patients at higher risk of death. 2. Indirectness: serious. There is substantial variability in baseline risk of mechanical ventilation between patients. Casirivimab-imdevimab may confer an important benefit in patients at higher risk of mechanical ventilation. 3. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 4. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 5. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 6. Imprecision: serious. 7. Indirectness: serious. Differences between the population of interest and those studied: the predominant strains currently circulating are not the same as the ones that were circulating during the studies. 8. Imprecision: very serious. Adverse effects leading to drug discontinuation Based on data from 5284 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 0 per 1000 0 fewer per 1000 CI 95% High Casirivimab-imdevimab do not result in an important increase in adverse effects leading to drug discontinuation. Allergic reactions Based on data from 15 406 participants in 4 studies. (Randomized controlled) 3 per 1000 Difference: 9 per 1000 6 more per 1000 ( CI 95% 1 fewer — 29 more ) Moderate Due to serious imprecision 6 Casirivimab-imdevimab probably do not result in an important increase in allergic reactions. Time to symptom resolution Lower better Based on data from 3084 participants in 2 studies. (Randomized controlled) 9 (Mean) Difference: 4.9 (Mean) MD 4.1 fewer ( CI 95% 5.7 fewer — 1.8 fewer ) Moderate Due to serious indirectness 7 Casirivimab-imdevimab probably reduce time to symptom improvement. Duration of hospitalization (not in hospital at baseline) Lower better Based on data from 111 participants in 2 studies. (Randomized controlled) 9.6 (Mean) Difference: 8.2 (Mean) MD 1.4 fewer ( CI 95% 4.6 fewer — 1.8 more ) Low Due to very serious imprecision 8 Casirivimab-imdevimab may not have an important impact on duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 80 of 142 For patients with severe or critical COVID-19 Practical Info Dosing and administration route: Intravenous dosing of the monoclonal antibody combination in the RECOVERY trial that enrolled severe and critical COVID-19 was a total dose of 8000 mg (4000 mg for each antibody), whereas the dose differed in the four trials in non-severe patients (from a larger adaptive randomized master protocol), ranging from intravenous total dose of 1200 mg–8000 mg. In the face of limited access and resource considerations, health systems will face a choice concerning the dose of casirivimab-imdevimab. Please see the acceptability and feasibility section (under Evidence to Decision) for deliberations to help in making these choices within the possible range of 2400 mg–8000 mg total dose. Diagnostic testing: Tests to identify patients with seronegative status at the time patients present with severe or critical COVID-19 warrant rapid serological tests with adequate performance characteristics. Health care systems would need to implement such tests, as outlined in the acceptability and feasibility section. Monitoring: Although the available trials have not convincingly shown that casirivimab-imdevimab results in allergic reactions, the possibility remains. Administer through an intravenous line containing a sterile in-line or add-on 0.2 micron filter. Following infusion, patients should undergo monitoring for allergic reactions. Evidence To Decision Conditional recommendation for We suggest treatment with casirivimab-imdevimab for patients with seronegative status, and where viral genotyping can confirm a susceptible SARS-CoV-2 variant (i.e. excluding Omicron BA.1) (conditional recommendation for). • With benefits of casirivimab-imdevimab observed only in patients with seronegative status, clinicians will need to identify these patients by credible tests available at the point of care to appropriately apply this recommendation (see Evidence to Decision section). • Treatment with casirivimab-imdevimab is in addition to the current standard of care, which includes corticosteroids and IL-6 receptor blockers. Updated In the overall population of patients with severe and critical COVID-19, casirivimab-imdevimab may not have an impact on mortality and the impact on mechanical ventilation and duration of hospitalization is very uncertain. A credible subgroup effect demonstrated that casirivimab-imdevimab probably reduces mortality in patients who are seronegative, with the absolute effects ranging from 39 fewer per 1000 (95% CI 62 fewer-13 fewer) in the severely ill to 69 fewer (95% CI 110 fewer-23 fewer) in the critically ill. In seronegative patients, the intervention possibly reduces the need for mechanical ventilation (absolute effect estimate 42 fewer per 1000; 95% CI 74 fewer-6 fewer). Aside from the credible subgroup effect for serological status, we 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. Benefits and harms In patients with severe and critical COVID-19, evidence for mortality was of low certainty because of imprecision and high likelihood that casirivimab-imdevimab has, 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 given additional concerns with risk of bias. For patients with severe and critical COVID-19 who are seronegative, evidence for mortality was rated as moderate as a result of concerns regarding imprecision (the confidence interval includes effects as small as 14 in 1000 that some patients may perceive as trivial) and indirectness (variants may emerge in which casirivimab-imdevimab antibodies may have reduced effect). For mechanical ventilation, the GDG noted risk of bias from lack of blinding as an additional concern, resulting in low certainty evidence. For duration of hospitalization, the GDG also found very serious imprecision, resulting in very low certainty evidence. Certainty of the Evidence Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 81 of 142 Applying the agreed values and preferences (see Section 7), the GDG inferred that most if not all well-informed patients with severe or critical COVID-19 and seronegative status would choose to receive casirivimab-imdevimab. Other patients – those whose are seropositive or whose status is uncertain – are likely to decline the intervention. Although the GDG focused on an individual patient perspective, they also considered a population perspective in which feasibility, acceptability, equity and cost are important considerations. In this case, feasibility concerns played an important role in the conditional recommendation. For the severe and critical patients, both limited availability of therapeutics and the requirement for serological testing as part of clinical decision-making to identify the seronegative patients proved important. Values and preferences Cost and availability Given the cost and availability of casirivimab-imdevimab, and the challenges associated with serological testing, the obstacles to ensuring access in low- and middle-income countries may prove formidable. Thus, the panel’s suggestion that patients who are seronegative receive the intervention may exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, the recommendations should provide a stimulus to engage all possible mechanisms to improve global access to the intervention. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. Acceptability and feasibility Supply of casirivimab-imdevimab is likely to be limited, raising accessibility and possibly rationing challenges. In addition, benefit requires identification of serological status at the time patients present with severe or critical COVID-19. The availability of rapid and accurate serological tests as well as dosing and administration route for the drug are therefore key factors to consider for health care systems. Rapid serological tests: Tests with performance characteristics similar to the reference standard test used to characterize seronegative patients in the RECOVERY trial, i.e. the Oxford fluorescent-based ELISA assay for serum IgG against the SARS- CoV-2 spike protein, with an arbitrary cut-off determined by a panel of positive controls, are available and potentially affordable. Some lateral flow assays may be suitable and can usually be performed in several minutes (106)(107)(108). Health care systems must, however, gain expertise in choosing and implementing a rapid test or test, choosing those most applicable to their setting.. Choosing a dose: The clinical trial in severe and critical patients (RECOVERY) tested a total dose of 8000 mg (4000 mg of each antibody) casirivimab-imdevimab; clinical trials in non-severe patients have used total doses of 1200 mg–8000 mg (600 mg–4000 mg of each) with similar effects on decreasing the need for hospitalization. Pharmacokinetic profiles of casirivimab-imdevimab in non-severe with COVID-19 are available at total doses of 1200 mg–8000 mg (600 mg–4000 mg of each monoclonal antibody) (104). This study demonstrated that the target therapeutic concentrations were achieved rapidly in serum and maintained for 28 days even at the lowest total dose of 1200 mg (600 mg of each antibody), although serum concentrations of the drug were noted to vary considerably between individuals. Therefore, using doses lower than used in the RECOVERY trial (8000 mg total dose) for treatment of severely and critically ill patients may achieve the same benefit. On the other hand, it is theoretically plausible but untested that pharmacokinetic differences in severe and critical patients, when compared with non-severe, may reduce drug exposure (see Mechanism of action). This would increase the risk of sub-optimal drug exposure in some individuals, which in turn could increase the risk of therapeutic failure and the emergence of viral resistance. In the absence of clinical data on treatment of severe and critical patients with doses lower than 8000 mg, making a choice on which dose to use can be informed by values and preferences. If one’s priority is ensuring effectiveness in every individual who receives treatment, and minimizing the risk of emergence of resistance, one might use the total intravenous dose of 8000 mg (4000 mg of each antibody). If one’s priority is, in the face of limited drug availability and high cost, giving as many people as possible an opportunity to benefit from treatment, one might use an intravenous dose as low as a total of 2400 mg (1200 mg of each antibody). At a time of drug shortage, it may be necessary to prioritize use of casirivimab-imdevimab through clinical triage. One possibility is to prioritize patients with the highest baseline risk for mortality (e.g. those with critical disease over those with Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 82 of 142 Justification In patients with severe or critical illness, the conditional recommendation in favour of casirivimab-imdevimab use reflects the likelihood that any benefits are restricted to patients who are seronegative. In the RECOVERY trial, which provided all the evidence in severe and critical patients, serological status at baseline was assessed in a pre-planned but retrospective analysis using a laboratory-based anti-spike protein assay. In order to translate the trial findings into clinical practice, assessment of serological status will need to become integrated into a clinical decision pathway before treatment is administered. 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 and relatively inexpensive tests with adequate performance characteristics are available and should see increasing use in settings in which casirivimab-imdevimab is available for administration to these patients. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. Fortunately, very few children become critically ill with COVID-19. For those who do and are seronegative, it is possible they may benefit from casirivimab-imdevimab. Lack of data precluded the GDG from making specific recommendations for other special populations, such as pregnant women. severe disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite consistent relative effects (OR 0.85 for mortality) with casirivimab-imdevimab in seronegative patients, the absolute risk reduction for mortality in the critically ill would be 69 fewer deaths per 1000 (95% CI 110 to 23 fewer deaths) and in the severely ill would be 39 fewer deaths per 1000 (95% CI 62 to 13 fewer deaths). Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course and avoiding casirivimab-imdevimab therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller). Clinical Question/ PICO Population: Patients with severe or critical COVID-19, seronegative Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary The LNMA was informed by one large trial (RECOVERY) in patients with severe and critical illness that enrolled 9785 patients, most of whom received corticosteroids (109). The trial was registered and presented in pre-prints when the data was reviewed by the GDG. The Table shows trial characteristics. The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with severe and critical COVID-19 and seronegative status, with certainty ratings. Specific considerations regarding baseline risk estimates informing absolute estimates of effect In severe and critical COVID-19 patients, for the critical outcome of mortality, the applied baseline risk estimate was 13% (130 in 1000). As for other related recommendations in this guideline, the estimate is derived from the SOLIDARITY trial for severe and critical patients adjusted for treatment effects of corticosteroids. To inform baseline risk estimates for mortality in seronegative patients, we identified the control arm of the RECOVERY trial as the best source. For patients with seronegative status, risk of death in both severe (26%; 260 per 1000) and critical (46%; 460 per 1000) illness is substantially higher than for the overall population. Thus, seronegative patients represent a very high risk population, leading to substantial absolute risk reductions in mortality (3.9% in the severe and 6.9% in the critical) despite the modest 15% relative risk reduction. Subgroup analysis A highly credible subgroup effect demonstrated that casirivimab-imdevimab likely reduces mortality in patients who are Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 83 of 142 seronegative but not in those who are seropositive. The credibility of the subgroup effect was evaluated using the ICEMAN tool (110). The credibility of the subgroup effect was strongly supported by: an a priori hypothesis with a specified direction; a small number of such hypotheses; evidence based on a within-study comparison; a suggestion of a similar subgroup effect in mechanical ventilation; and an interaction p-value of 0.001. Fig. 2 presents the forest plot depicting the point estimate and confidence interval around the effects on mortality in patients with seropositive and seronegative status, demonstrating benefit in those with seronegative status, suggesting harm in those with seropositive status, and no overlap in the confidence intervals, a result corresponding to the p=0.001 in the test of interaction (109). Fig. 2. Mortality, in seropositive and seronegative patients with severe and critical COVID-19 CI: confidence interval, RR: relative risk. Very low certainty evidence raises the possibility of shorter hospitalization in seronegative patients. Aside from the reported subgroup effects on serological status, we found no evidence of subgroup effects on age, time from onset of illness, and severity (comparing severe and critically ill patients). Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Severe disease Relative risk 0.85 (CI 95% 0.76 — 0.95) Based on data from 2823 participants in 1 study. (Randomized controlled) 260 per 1000 Difference: 221 per 1000 39 fewer per 1000 ( CI 95% 62 fewer — 13 fewer ) Moderate Due to concerns with imprecision and indirectness 1 Casirivimab-imdevimab probably reduce mortality. Mortality Critical disease Relative risk 0.85 (CI 95% 0.76 — 0.95) Based on data from 2823 participants in 1 study. (Randomized controlled) 460 per 1000 Difference: 391 per 1000 69 fewer per 1000 ( CI 95% 110 fewer — 23 fewer ) Moderate Due to concerns with imprecision and indirectness 2 Casirivimab-imdevimab probably reduce mortality. Mechanical ventilation Relative risk 0.87 (CI 95% 0.77 — 0.98) Based on data from 2410 participants in 1 study. (Randomized controlled) 320 per 1000 Difference: 278 per 1000 42 fewer per 1000 ( CI 95% 74 fewer — 6 fewer ) Low Due to concerns with risk of bias, imprecision, and indirectness 3 Casirivimab-imdevimab may reduce mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 84 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. Single study. 2. Imprecision: serious. Single study. 3. Risk of bias: serious. Imprecision: serious. 4. Risk of bias: serious. Indirectness: serious. Imprecision: very serious. Duration of hospitalization Based on data from 3153 participants in 1 study. (Randomized controlled) The median duration of hospital stay was 4 days shorter with casirivimab- imdevimab (13 days vs. 17 days). Very low Due to serious risk of bias, serious indirectness, and very serious imprecision 4 The impact on duration of hospitalization is very uncertain. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Casirivimab-imdevimab Comparator: Standard care Summary Evidence summary The NMA evidence summary was informed by one large trial (RECOVERY) in patients with severe and critical illness that enrolled 9785 patients, most of whom received corticosteroids (109). The trial was registered and presented in preprints when the data was reviewed by the GDG. The Table shows trial characteristics. The GRADE Summary of Findings table shows the relative and absolute effects of casirivimab-imdevimab compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Critical or severe disease Odds ratio 0.94 (CI 95% 0.86 — 1.03) Based on data from 9785 participants in 1 study. (Randomized controlled) 130 per 1000 Difference: 122 per 1000 8 fewer per 1000 ( CI 95% 18 fewer — 4 more ) Low Due to serious indirectness and imprecision 1 Casirivima-imdevimab may not have an important effect on mortality. Mechanical ventilation Odds ratio 0.95 (CI 95% 0.87 — 1.04) Based on data from 6637 participants in 1 study. (Randomized controlled) 86 per 1000 Difference: 82 per 1000 4 fewer per 1000 ( CI 95% 11 fewer — 3 more ) Very low Due to serious risk of bias, indirectness, and imprecision 2 The impact on mechanical ventilation is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 85 of 142 6.10.1 Mechanism of action Casirivimab and imdevimab are two fully human antibodies (REGN10933 and REGN10987). Their mechanism of action is very plausible: they bind to the SARS-CoV-2 spike protein (111) and have demonstrated antiviral activity in rhesus macaques and Syrian golden hamsters (112). Pharmacokinetic data in patients with non-severe COVID-19 show that antiviral concentrations of both antibodies are achieved and maintained for at least 28 days after intravenous administration of the combination at a total dose of 1200 mg (600 mg each antibody) or above (42). Antiviral concentrations are also achieved and maintained using a subcutaneous total dose of 1200 mg (600 mg of each antibody) in uninfected individuals for prophylaxis (105). Half-lives range from 25 to 37 days for both antibodies. Data are currently unavailable for the pharmacokinetics of casirivimab and imdevimab in severe and critical COVID-19, which are important because serum concentrations of other monoclonal antibodies have been reported to be lower during systemic inflammation and correlated with albumin and CRP levels (113). Data available also suggest that when delivered in combination, activity remains for currently circulating variants of concern (114). While the mechanism is plausible, it was postulated that administration might have differential effects in patients who have produced their own anti-SARS-CoV-2 spike protein antibodies (hereafter seropositive) compared with those who have not (hereafter seronegative). It was hypothesized that effects might be larger, or restricted to, seronegative individuals who have not yet mounted an effective antibody response. Data describing the in vitro neutralization of different variants by monocolonal antibodies are collated on the NIH NCATS OpenData Portal (https://opendata.ncats.nih.gov/variant/activity). Several reports have demonstrated that in vitro neutralization of pseudovirus containing the BA.1 Omicron spike protein and in vitro neutralization of authentic BA.1 Omicron virus is dramatically reduced or lost for casirivumab and imdevimab when studied individually, and completely lost when both monoclonal antibodies are combined. Furthermore, the combination of casirivumab and imdevimab has no impact upon subgenomic viral RNA in the lungs or nasal turbinate of K18 human ACE2 transgenic mice infected with BA.1 Omicron Outcome Timeframe Study results and measurements Comparator Standard care Intervention Casirivimab- imdevimab Certainty of the Evidence (Quality of evidence) Plain language summary 1. Indirectness: serious. Imprecision: serious. 2. Risk of bias: serious. Indirectness: serious. Imprecision: serious. 3. Imprecision: serious. 4. Risk of bias: serious. Imprecision: very serious. Allergic reactions Based on data from 15 406 participants in 4 studies. (Randomized controlled) 3 per 1000 Difference: 9 per 1000 6 more per 1000 ( CI 95% 1 fewer — 29 more ) Moderate Due to serious imprecision 3 Casirivimab-imdevimab probably do not result in an important increase in allergic reactions. Adverse effects leading to drug discontinuation Based on data from 5284 participants in 4 studies. (Randomized controlled) 2 per 1000 Difference: 1 per 1000 1 fewer per 1000 ( CI 95% 0 more — 1 more ) High Casirivimab-imdevimab do not result in an important increase in adverse effects leading to drug discontinuation. Duration of hospitalization Based on data from 9785 participants in 1 study. (Randomized controlled) Patients in both groups had the same median duration of hospitalization (10 days). Very low Due to serious risk of bias and very serious imprecision 4 The impact on duration of hospitalization is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 86 of 142 do not support activity of the casirivumab and imdevimab combination against the BA.1 Omicron variant. 6.11 Interleukin-6 receptor blockers (published 6 July 2021) For patients with severe or critical COVID-19 Practical Info Route: IL-6 receptor blockers are administered intravenously for the treatment of patients with severe or critical COVID-19; subcutaneous administration is not used in this case. IL-6 receptor blocker therapy should be administered in combination with systemic corticosteroids, which may be administered both orally and intravenously, with due consideration to their high bioavailability but possible malabsorption in the case of intestinal dysfunction with critical illness. Duration: Tocilizumab and sarilumab are administered as single intravenous doses, typically over 1 hour. A second dose may be administered 12 to 48 hours after the first dose; this was offered variably in major clinical trials at the discretion of treating clinicians if a clinical response was felt to be inadequate. Duration of concurrent systemic corticosteroids is typically up to 10 days, though may vary between 5 and 14 days. Dose: Tocilizumab is dosed at 8 mg per kilogram of actual body weight, up to a maximum of 800 mg. Sarilumab is most commonly dosed at 400 mg, consistent with what was used in REMAP-CAP. Renal dose adjustment is not currently warranted for either drug. Monitoring: Routine bloodwork including neutrophil count, platelets, transaminases, and total bilirubin should be checked prior to initiation of therapy. All patients should be monitored for signs and symptoms of infection, given the increased risk with immunosuppression in addition to systemic corticosteroids. Patients on longer term IL-6 receptor blocker therapy are at risk of active tuberculosis, invasive fungal infections and opportunistic pathogens. Risks and benefits of therapy should be considered carefully in patients with any active, severe infection other than COVID-19; caution is advised when considering the use of tocilizumab in patients with a history of recurring or chronic infections or with underlying conditions which may predispose them to infections. Timing: IL-6 receptor blockers should be initiated with systemic corticosteroids; specific timing during hospitalization or the course of illness is not specified. That being said, IL-6 receptor blockers have been administered early in the course of Info Box The recommendation concerning IL-6 receptor blockers (tocilizumab or sarilumab) was published on 6 July 2021 as the fifth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the publication of RECOVERY and REMAP-CAP trial publications in February 2021, and new trial data from 1020 patients randomized head-to-head to either tocilizumab or sarilumab in REMAP-CAP being made available to the WHO on 1 June 2021. No changes were made to the IL-6 receptor blocker recommendation in this eleventh version of the guideline. WHO has made a strong recommendation for JAK inhibitors, specifically baricitinib, in patients with severe and critical COVID-19. An IL-6 receptor blocker and baricitinib should not be given together and should be viewed as alternatives. These new considerations are provided under ‘Justification’ for the recommendation for IL-6 receptor blockers, and are unchanged in this eleventh version of the guideline. Strong recommendation for We recommend treatment with IL-6 receptor blockers (tocilizumab or sarilumab) (strong recommendation for). • Corticosteroids have previously been strongly recommended in patients with severe and critical COVID-19 (see Section 6.15), and we recommend patients meeting these severity criteria should now receive both corticosteroids and IL-6 receptor blockers. • Baricitinib, a JAK inhibitor, is now recommended for the treatment of patients with severe and critical COVID-19 (see Section 6.7). An IL-6 receptor blocker and baricitinib should not be given together and should be viewed as alternatives. The choice of whether to use baricitinib or an IL-6 receptor blocker depends on availability as well as clinical and contextual factors (see Justification). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 87 of 142 (https://www.biorxiv.org/content/10.1101/2022.01.23.477397v1.full.pdf+html). Therefore, currently available preclinical data hospitalization in the included trials and clinicians may consider this approach if possible. See section on resource implications, equity and human rights. Evidence To Decision IL-6 receptor blockers reduce mortality and need for mechanical ventilation based on high certainty evidence. Low certainty evidence suggests they may also reduce duration of mechanical ventilation and hospitalization (3)(115)(116). The evidence regarding the risk of serious adverse events (SAEs) is uncertain. Low certainty evidence suggested that the risk of bacterial infections in the context of immunosuppression treatment with IL-6 receptor blockers may be similar to usual care (1). However the GDG had some concerns that, given the short-term follow-up of most trials and the challenges associated with accurately capturing adverse events such as bacterial or fungal infection, the evidence summary may under- represent the risks of treatment with IL-6 receptor blockers. Furthermore, the trials of IL-6 receptor blockers that inform this recommendation were mostly performed in high-income countries where the risk of certain infectious complications may be less than in some other parts of the world, and so the generalizability of the data on adverse events is unclear. We did not have any data examining differential risk of harm based on whether patients received one or two doses of IL-6 receptor blocker. Subgroup analyses indicated no effect modification based on IL-6 receptor blocker drug (sarilumab or tocilizumab) or disease severity (critical vs severe) and therefore this recommendation applies to all adult patients with either severe or critical COVID-19 (110). We were unable to examine subgroups based on elevation of inflammatory markers or age due to insufficient trial data (see Research evidence). Subgroup analyses evaluating baseline steroid use found greater benefit of IL-6 receptor blockers in patients receiving steroids compared with those who were not (p=0.026), demonstrating that steroid use does not abolish and might enhance the beneficial effect of IL-6 receptor blockers. Since steroids are already strongly recommended in patients with severe and critical COVID-19, we did not formally evaluate the credibility of this subgroup analysis as there would be no rationale for a subgroup recommendation for patients not receiving corticosteroids. Benefits and harms Certainty of evidence was rated as high for mortality and need for mechanical ventilation. Certainty in duration of mechanical ventilation was rated as low due to serious risk of bias due to concerns regarding lack of blinding in included trials, and for imprecision as the lower limit of the confidence interval suggested no effect. Certainty in duration of hospitalization was rated as low due to serious risk of bias from lack of blinding in included trials, and for inconsistency related to differences in point estimates and lack of overlap in confidence intervals. Certainty in serious adverse events was rated as very low due to risk of bias related to lack of blinding and ascertainment bias, and very serious imprecision due to very wide confidence intervals which did not rule out important benefit or harm; certainty in risk of bacterial or fungal infections was rated as low due to similar concerns regarding serious risk of bias and serious imprecision. Certainty in evidence was rated as moderate when comparing the effect on mortality between tocilizumab and sarilumab due to issues with imprecision. Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the majority of the GDG inferred that almost all well-informed patients would want to receive IL-6 receptor blockers. The benefit of IL-6 receptor blockers on mortality was deemed of critical importance to patients, despite the very low certainty around serious adverse events. The GDG anticipated little variation in values and preferences between patients for this intervention. Values and preferences Resource implications, equity and human rights Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 88 of 142 Justification When moving from evidence to the strong recommendation to use IL-6 receptor blockers (tocilizumab or sarilumab) in patients with severe or critical COVID-19, the GDG emphasized the high certainty evidence of improved survival and reduction in need for mechanical ventilation. Additional trial data from REMAP-CAP (see Research Evidence section) provided more conclusive evidence regarding the equivalence of tocilizumab and sarilumab. The GDG acknowledged the uncertain data regarding SAEs and bacterial infections, but felt that the evidence of benefit for the two most important patient outcomes warranted a strong recommendation. Costs and access were important considerations and it was recognized that this recommendation could exacerbate health inequities. Hopefully this strong recommendation will provide impetus to address these concerns and ensure access across regions and countries. The GDG did not anticipate important variability in patient values and preferences, and judged that other contextual factors would not alter the recommendation (see Evidence to Decision). Subgroup analyses The GDG did not find any evidence of a subgroup effect across patients with different levels of disease severity (severe vs critical), or by IL-6 receptor blocker drug (tocilizumab vs sarilumab). There were insufficient data to assess subgroup effect by elevation of inflammatory markers or age. Although the GDG considered a subgroup analysis of patients receiving corticosteroids at baseline as compared with those that were not, the panel did not see a need to consider subgroup recommendations for IL-6 receptor blockers in those not receiving corticosteroids as all severe and critical COVID-19 patients should be receiving corticosteroids (see previous strong recommendation below). Taken together, the GDG felt that the recommendation applies to both tocilizumab and sarilumab and all adult patients with severe or critical COVID-19. The role of IL-6 receptor blockers and baricitinib WHO has recently made a strong recommendation for baricitinib in patients with severe and critical COVID-19. Both classes of drugs are immune modulators with overlapping effects on immune responses. There is therefore a reasonable possibility that their effects on COVID-19 will not be additive. Moreover, it is possible that when given together, adverse effects, including secondary bacterial or fungal infection, will be greater. In the absence of evidence of incremental benefit of the drugs when given together, the GDG advises that clinicians do not administer the drugs together. See Justification section for JAK inhibitors and related Summary of Findings table (see Research evidence) for more detailed discussion regarding selecting between therapies. The GDG noted that, compared with some other candidate treatments for COVID-19, IL-6 receptor blockers are more expensive and the recommendation does not take account of cost-effectiveness. Currently, access to these drugs is challenging in many parts of the world, and without concerted effort is likely to remain so, especially in resource-poor areas. It is therefore possible that this strong recommendation for IL-6 receptor blockers could exacerbate health inequity. On the other hand, given the demonstrated benefits for patients, it should also provide a stimulus to engage all possible mechanisms to improve global access to these treatments. Individual countries may formulate their guidelines considering available resources and prioritize treatment options accordingly. At a time of drug shortage, it may be necessary to prioritize use of IL-6 receptor blockade through clinical triage (6). Many jurisdictions have suggested mechanisms for triaging use of these treatments. These include prioritizing patients with the highest baseline risk for mortality (e.g. those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. For example, despite consistent relative effects (OR 0.86 for mortality) with IL-6 receptor blockers, the absolute risk reduction for mortality in the critically ill would be 31 fewer deaths per 1000 (95% CI 11 to 47 fewer deaths) and in the severely ill would be 13 fewer deaths per 1000 (95% CI 5 to 19 fewer deaths). Other suggestions for prioritization, which lack direct evidence, include focusing on patients with an actively deteriorating clinical course and avoiding IL-6 receptor blocker therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller). Acceptability and feasibility As IL-6 receptor blockers require intravenous administration, this treatment would be primarily indicated for patients with severe and critical COVID-19 who require hospitalization. IL-6 receptor blockers are relatively easy to administer, and only require one, or at most, two doses. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 89 of 142 Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the GDG had no reason to think that children with COVID-19 would respond any differently to treatment with IL-6 receptor blockers. This is especially true given tocilizumab is used in children safely for other indications including polyarticular juvenile rheumatoid arthritis, systemic onset of juvenile chronic arthritis, and chimeric antigen receptor T-cell induced cytokine release syndrome. Sarilumab is not approved in children, so if an IL-6 receptor blocker is used in this population, tocilizumab is preferred. The GDG also recognized that in many settings children are commonly admitted to hospital with acute respiratory illnesses caused by other pathogens; as a result, it may be challenging to determine who is ill with severe COVID-19, even with a positive test, and therefore likely to benefit from IL-6 receptor blockade. There were similar considerations in regard to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. The drug may, however, cross the placental membrane, although it is uncertain what effect transient immunosuppression in the fetus may have and this should be weighed against the potential benefit for the mother. Clinical Question/ PICO Population: Patients with severe and critical COVID-19 Intervention: Baricitinib Comparator: Interleukin-6 receptor blockers Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.77 (CI 95% 0.53 — 1.1) Based on data from 2659 participants in 3 studies. (Randomized controlled) 118 per 1000 Difference: 96 per 1000 22 fewer per 1000 ( CI 95% 52 fewer — 9 more ) Low Due to serious imprecision and ongoing recruitment in a large RCT 1 Baricitinib may reduce mortality. Mechanical ventilation Odds ratio 1.01 (CI 95% 0.61 — 1.6) Based on data from 2434 participants in 2 studies. (Randomized controlled) 94 per 1000 Difference: 96 per 1000 2 more per 1000 ( CI 95% 38 fewer — 44 more ) Low Due to very serious imprecision 2 There may be little or no difference on mechanical ventilation. Adverse effects leading to drug discontinuation Based on data from 2309 participants in 4 studies. (Randomized controlled) 0 per 1000 Difference: 1 per 1000 1 more per 1000 ( CI 95% 11 fewer — 15 more ) Moderate Due to serious imprecision 3 There is probably little to no difference in adverse effects leading to discontinuation. Hospital length of stay Lower better Based on data from 2652 participants in 3 studies. (Randomized controlled) 8.1 days (Median) Difference: 11.2 days (Mean) MD 3.1 more ( CI 95% 3.8 fewer — 9.9 more ) Very low Due to serious risk of bias, serious inconsistency, and very serious imprecision 4 The impact on hospital length of stay is very uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 90 of 142 Outcome Timeframe Study results and measurements Comparator IL-6 receptor blockers Intervention Baricitinib Certainty of the Evidence (Quality of evidence) Plain language summary 1. Imprecision: serious. The credible interval includes no important difference. 2. Risk of bias: no serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: very serious. The credible interval includes important benefit and important harm. 3. Imprecision: serious. The credible interval includes small but important harm. 4. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Inconsistency: serious. The trials that studied interleukin-6 receptor blockers had discrepant results: some increased length of stay, others reduced length of stay. Imprecision: very serious. The credible interval includes important benefit and important harm. 5. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. The credible interval includes no important difference. 6. Risk of bias: serious. Most of the data on interleukin-6 receptor blockers comes from trials that were unblinded. Imprecision: serious. Credible interval includes important harm and important benefit (using a minimal important difference threshold of 1 day). Duration of mechanical ventilation Lower better Based on data from 328 participants in 2 studies. (Randomized controlled) 13.8 days (Median) Difference: 11.6 days (Mean) MD 2.2 fewer ( CI 95% 5.3 fewer — 0.7 fewer ) Low Due to serious risk of bias and imprecision 5 Baricitinib may reduce duration of mechanical ventilation. Time to clinical stability Lower better Based on data from 2558 participants in 2 studies. (Randomized controlled) 8.4 days (Median) Difference: 8.9 days (Mean) MD 0.5 more ( CI 95% 2.3 fewer — 3.2 more ) Low Due to serious risk of bias and imprecision 6 There may not be an important impact on time to clinical stability. Clinical Question/ PICO Population: Patients with severe or critical COVID-19 Intervention: Interleukin-6 receptor blockers Comparator: Standard care Summary Evidence summary The LNMA (8) on IL-6 receptor blockers was informed by 30 RCTs with 10 618 participants and provided relative estimates of effect for all patient-important outcomes except mortality, which came from the prospective meta-analysis (PMA) (116). Of the trials included in the LNMA, all were registered and examined patients with severe or critical illness related to COVID-19 (trial characteristics table available upon request). Of the trials, 37% were published in peer- reviewed journals, 3% were available as preprints and 60% were completed but unpublished. The evidence summary for mortality was based on 27 RCTs and 10 930 participants from the PMA (116). We used the PMA for mortality as it included some additional unpublished data that reported on this outcome. The GDG recognized that usual care is likely variable between centres and regions, and has evolved over time. However, given all of the data come from RCTs, use of these co-interventions that comprise usual care would be expected to be balanced between study patients randomized to either the intervention or usual care arms. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 91 of 142 The GRADE Summary of Findings table shows the relative and absolute effects of IL-6 receptor blockers compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis All included RCTs evaluated IL-6 receptor blockers exclusively in severely or critically ill adults with COVID-19 requiring hospitalization. The GDG requested subgroup analyses based on age (< 70 years versus older), disease severity (severe versus critical), levels of inflammatory markers and baseline corticosteroid use for the following outcomes: mortality, need for and duration of mechanical ventilation, duration of hospitalization, and risks of SAEs and bacterial infections. Based on subgroup analyses, the GDG determined that there was no subgroup effect across any pre-specified outcomes of interest based on disease severity. The GDG considered the results of a subgroup analysis of all included RCTs based on systemic corticosteroid use for the outcome of mortality. The analysis suggested that the relative effects of IL-6 receptor blockers varied as a function of the use of systemic corticosteroids at baseline. Crucially, steroids did not abolish and may even enhance the beneficial effect of IL-6 receptor blockers on mortality. For reasons described below, the GDG did not formally evaluate the credibility of this subgroup analysis. When comparing tocilizumab and sarilumab, based on the PMA, there was no evidence of a subgroup effect (116). However, there were more data, and therefore greater precision, for tocilizumab+steroids versus steroids alone (OR 0.77, 95% CI 0.68–0.87) as compared with sarilumab+steroids versus steroids alone (OR 0.92, 95% CI 0.61–1.38). In addition to these subgroup data, the GDG reviewed head-to-head data from REMAP-CAP investigators which demonstrated no difference between tocilizumab as compared with sarilumab in a population of patients all receiving corticosteroids (36.5% mortality with tocilizumab, 33.9% mortality with sarilumab). The NMA estimate of tocilizumab+steroids versus sarilumab+steroids, incorporating both direct and indirect data, provided moderate certainty data of no difference between the drugs (OR 1.07, 95% CI 0.86–1.34) (1)(3). Outcome Timeframe Study results and measurements Comparator Standard care Intervention IL-6 receptor blockers Certainty of the Evidence (Quality of evidence) Plain language summary Mortality (severe and critically ill patients) Odds ratio 0.86 (CI 95% 0.79 — 0.95) Based on data from 10 930 participants in 27 studies. 1 (Randomized controlled) 130 per 1000 Difference: 114 per 1000 16 fewer per 1000 ( CI 95% 24 fewer — 6 fewer ) High IL-6 receptor blockers reduce mortality. Mechanical ventilation Odds ratio 0.72 (CI 95% 0.57 — 0.9) Based on data from 5686 participants in 9 studies. 2 (Randomized controlled) 86 per 1000 Difference: 63 per 1000 23 fewer per 1000 ( CI 95% 35 fewer — 8 fewer ) High IL-6 receptor blockers reduce need for mechanical ventilation. Adverse events leading to drug discontinuation Odds ratio 0.5 (CI 95% 0.03 — 9.08) Based on data from 815 participants in 2 studies. 3 (Randomized controlled) 9 per 1000 Difference: 5 per 1000 4 fewer per 1000 ( CI 95% 0 more — 67 more ) Very low Due to serious risk of bias and very serious imprecision 4 The effect of IL-6 receptor blockers on adverse events leading to discontinuation is uncertain. Bacterial infections Odds ratio 0.95 (CI 95% 0.72 — 1.29) Based on data from 101 per 1000 96 per 1000 Low Due to serious risk of bias and IL-6 receptor blockers may not increase secondary bacterial Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 92 of 142 6.11.1 Mechanism of action IL-6 is a pleiotropic cytokine which activates and regulates the immune response to infections. Elevated IL-6 concentrations are associated with severe outcomes in COVID-19, including respiratory failure and death, although the role of IL-6 in disease pathogenesis is unclear. Tocilizumab and sarilumab are monoclonal antibodies approved for use in rheumatoid arthritis. They antagonize the membrane bound and soluble forms of the IL-6 receptor (IL-6R/sIL-6R). Tocilizumab is approved for intravenous use in rheumatoid arthritis Outcome Timeframe Study results and measurements Comparator Standard care Intervention IL-6 receptor blockers Certainty of the Evidence (Quality of evidence) Plain language summary 1. . Baseline/comparator: Primary study[15]. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19, adjusted for corticosteroids as part of standard of care (16% baseline risk x RR 0.79 for corticosteroids = 13%). The control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, was identified by the GDG panel as generally representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19. 2. Systematic review [3] . Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19, adjusted for corticosteroids as part of standard of care (16% baseline risk x RR 0.79 for corticosteroids = 13%). The control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, was identified by the GDG panel as generally representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation for severely and critically ill patients with COVID-19. 3. Systematic review. Baseline/comparator: Control arm of reference used for intervention. We used the median event rate for all patients randomized to usual care across included studies. Supporting references: [3], 4. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding and ascertainment bias. Imprecision: very serious. We downgraded due to very wide confidence intervals crossing the null. 5. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding and ascertainment bias. Imprecision: serious. Downgraded due to wide confidence intervals crossing the null. 6. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding. Imprecision: serious. We downgraded as the lower limit of the confidence interval was close to the null. 7. Risk of bias: serious. We downgraded for some concerns regarding risk of bias due to lack of blinding. Inconsistency: serious. Downgraded due to differences in point estimates and lack of overlap in confidence intervals. 3548 participants in 18 studies. (Randomized controlled) Difference: 5 fewer per 1000 ( CI 95% 26 fewer — 26 more ) serious imprecision 5 infections. Duration of mechanical ventilation Lower better Based on data from 1189 participants in 10 studies. (Randomized controlled) 14.7 (Mean) Difference: 13.5 (Mean) MD 1.2 lower ( CI 95% 2.3 lower — 0.1 lower ) Low Due to serious risk of bias and serious imprecision 6 IL-6 receptor blockers may reduce duration of mechanical ventilation. Duration of hospitalization Lower better Based on data from 6665 participants in 9 studies. (Randomized controlled) 12.8 (Mean) Difference: 8.3 (Mean) MD 4.5 lower ( CI 95% 6.7 lower — 2.3 lower ) Low Due to serious risk of bias and serious inconsistency 7 IL-6 receptor blockers may reduce duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 93 of 142 and sarilumab for subcutaneous use, although in COVID-19 both have been studied intravenously. At the studied doses in COVID-19, both medicines are expected to achieve very high levels of receptor occupancy based upon studies in rheumatoid arthritis (29). IL-6 receptor blockers are being repurposed in terms of indication but not in terms of the primary pharmacological mechanism of action. Efficacy in COVID-19 depends upon the importance of IL-6 signalling in the pathophysiology of the disease, rather than upon whether the doses used achieve target concentrations. 6.12 Ivermectin (published 31 March 2021) For patients with COVID-19, regardless of disease severity Practical Info The GDG made a recommendation against using ivermectin for treatment of patients with COVID-19 outside the setting of a clinical trial and therefore practical considerations are less relevant for this drug. Evidence To Decision Info Box The recommendation concerning ivermectin was published on 31 March 2021 as the fourth version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the increased international attention on ivermectin as a potential therapeutic option. No changes were made to the ivermectin recommendation in this eleventh version of the guideline. We are aware of a few new, relatively small trials published since our recommendation was made and that one key trial has since been retracted given concerns about research fraud (117)(118). However, the updated evidence summary from the LNMA is consistent with our previously made recommendation. This updated evidence summary will be fully considered by the GDG in subsequent iterations of the guideline. Only in research settings We recommend not to use ivermectin, except in the context of a clinical trial (recommended only in research settings). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. A recommendation to only use a drug in the setting of clinical trials is appropriate when there is very low certainty evidence and future research has a large potential for reducing uncertainty about the effects of the intervention and for doing so at reasonable cost. The effects of ivermectin on mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral clearance remain uncertain because of very low certainty of evidence addressing each of these outcomes. Ivermectin may have little or no effect on time to clinical improvement (low certainty evidence). Ivermectin may increase the risk of SAEs leading to drug discontinuation (low certainty evidence). Subgroup analyses indicated no effect modification based on dose. We were unable to examine subgroups based on patient age or severity of illness due to insufficient trial data (see Research evidence). Therefore, we assumed similar effects in all subgroups. This recommendation applies to patients with any disease severity and any duration of symptoms. Benefits and harms For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral Certainty of the Evidence Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 94 of 142 Justification When moving from evidence to a recommendation on the use of ivermectin in patients with COVID-19 only in the context of a clinical trial, the GDG emphasized the high degree of uncertainty in the most critical outcomes such as mortality and need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased adverse events. The GDG did not anticipate important variability in patient values and preferences. Other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity did not alter the recommendation. Compared with previous drugs evaluated as part of the WHO Therapeutics and COVID-19: living guideline, currently there are far fewer RCT data available for ivermectin. The existing data on ivermectin also have a substantially higher degree of uncertainty, with included trials having enrolled substantially fewer patients with far fewer events. High degree of uncertainty The certainty in effect estimates for ivermectin on the main outcomes of interest, including mortality, is very low and therefore the effect of ivermectin on these outcomes remains uncertain. There are two domains that contribute to this uncertainty: serious risk of bias; and serious imprecision. Although 16 RCTs contributed to the evidence summary informing this drug, only five directly compared ivermectin with standard of care and reported mortality (119)(120)(121)(122)(123)(124)(125). Of note, and in keeping with our methodology, the LNMA team excluded quasi-randomized trials, or any RCT that did not use explicit randomization techniques. Of these five RCTs, two (119)(120) were at high risk of bias, due to inadequate blinding. One of these two trials (119) also started enrolling and randomizing patients prior to the protocol being publicly posted, another factor that contributes to an increased risk of bias. The potential impact of risk of bias is exemplified by subgroup analyses for mortality based on trial risk of bias. As demonstrated in the forest plot (Fig. 3), the pooled estimate across all five RCTs that directly compare ivermectin with standard care suggests a reduction in mortality with ivermectin, but this effect is not apparent if we only consider the trials at low risk of bias (which together contribute nearly two-thirds of the evidence). This finding increases the degree of uncertainty regarding the true effect of ivermectin on mortality. Consistent with the direct evidence, a similar phenomenon is observed with the indirect evidence comparing ivermectin to standard of care (via comparisons against clearance, the GDG considered the evidence of very low certainty. Evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also serious concerns related to risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias). For more details, see the Justification section for this recommendation. For other outcomes, including SAEs and time to clinical improvement, the certainty of the evidence was low. Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would want to receive ivermectin only in the context of a randomized trial, given that the evidence left a very high degree of uncertainty in effect on mortality, need for mechanical ventilation, need for hospitalization and other critical outcomes of interest and there was a possibility of harms, such as treatment-associated SAEs. The panel anticipated little variation in values and preferences between patients when it came to this intervention. Values and preferences Ivermectin is a relatively inexpensive drug and is widely available, including in low-income settings. The low cost and wide availability do not, in the GDG's view, mandate the use of a drug in which any benefit remains very uncertain and ongoing concerns regarding harms remain. Although the cost may be low per patient, the GDG raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe COVID-19 and other supportive care interventions. Also, use of ivermectin for COVID-19 would divert drug supply away from pathologies for which it is clearly indicated, potentially contributing to drug shortages, especially for helminth control and elimination programmes. Other endemic infections that may worsen with corticosteroids should be considered. If steroids are used in the treatment of COVID-19, empiric treatment with ivermectin may still be considered in Strongyloidiasis endemic areas, at the discretion of clinicians overseeing treatment, albeit not for treatment of COVID-19 itself. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 95 of 142 hydroxychloroquine and lopinavir/ritonavir). The indirect evidence suggesting a reduction in mortality with ivermectin is driven almost entirely by one study which is at high risk of bias (117) due to a lack of detailed description of blinding or randomization and the lack of a publicly available study protocol (figure not shown). Fig. 3. Forest plot demonstrating direct comparison of ivermectin versus standard of care for mortality with subgroup analysis by risk of bias IV: inverse variance. In addition to concerns related to risk of bias, for the outcome of mortality, there are very serious concerns related to imprecision. According to GRADE, imprecision is evaluated based on both a confidence interval approach and an evaluation of information size (event number), ensuring there is adequate information on which to make informed judgments (126). In this case, despite confidence intervals that suggest benefit with ivermectin, the information size is very low. For mortality (and ignoring the concerns related to risk of bias discussed above), there were nine deaths across all 511 patients randomized to ivermectin (1.76%) and 22 deaths across all 404 patients randomized to standard of care (5.45%). This is an extremely small number of events on which to base conclusions, and far below the optimal information size. In fact, performing a theoretical exercise in which a change of three events (deaths) is made from those randomized to standard of care to those randomized to ivermectin eliminates any statistical significance, a finding that suggests that results could reasonably be due to chance alone. Furthermore, the evidence informing this comparison is from multiple small trials, adding to the risk of unrecognized imbalances in study arms. Given the strong likelihood that chance may be playing a role in the observed findings, the panel believed there was very serious imprecision further lowering the overall certainty in findings. This combination of serious risk of bias and very serious imprecision contributed to very low certainty of evidence for mortality despite a point estimate and confidence interval that appear to suggest benefit with ivermectin. As a result, the panel concluded that the effect of ivermectin on mortality is uncertain. Similar considerations were applied to the other critical outcomes including mechanical ventilation, hospital admission, and duration of hospitalization and resulted in very low certainty for these outcomes as well. Subgroup analyses We conducted subgroup analysis only for effect by ivermectin dose and the panel did not find any evidence of a subgroup effect (see Research evidence). A lack of within-trial comparisons prevented subgroup analyses by age or disease severity. Therefore, the panel did not make any subgroup recommendation for this drug. In other words, the recommendation against ivermectin except in the context of clinical trials is applicable across disease severity, age groups, and all dose regimens of ivermectin. Applicability None of the included RCTs enrolled children under 15, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with ivermectin. There were similar considerations for pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently to other adults. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 96 of 142 Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Ivermectin Comparator: Standard care Summary Evidence summary The LNMA on ivermectin was based on 16 RCTs and 2407 participants. Of the included studies, 75% examined patients with non-severe disease and 25% included both severe and non-severe patients. A number of the included studies did not report on our outcomes of interest. Of the studies, 25% were published in peer-reviewed journals, 44% were available as preprints and 31% were completed but unpublished (see Table on trial characteristics). We excluded a number of quasi-RCTs (127)(128)(129)(130). The GRADE Summary of Findings table shows the relative and absolute effects of ivermectin compared to usual care for the outcomes of interest in patients with COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis The NMA team performed subgroup analyses which could result in distinct recommendations by subgroups. From the available data, subgroup analyses were only possible by dose of ivermectin and considering the outcomes of mortality, mechanical ventilation, admission to hospital, and adverse events leading to drug discontinuation. The ivermectin dose subgroup analyses were performed from the direct comparison of ivermectin versus usual care. For these analyses, meta-regression was used to evaluate the effect of cumulative dose as a continuous variable, and further adding a co- variate for single vs multiple dosing regimens. This approach was based on input from the pharmacology experts (led by Professor Andrew Owen) who performed pharmacokinetic simulations across trial doses, and found that cumulative ivermectin dose was expected to correlate with key pharmacokinetic parameters when single- and multiple-dose studies were segregated. It should be noted that the included trials did not directly assess the pharmacokinetics of ivermectin, and our approach was based upon simulations validated where possible against published pharmacokinetics in humans. The panel used a pre-specified framework incorporating the ICEMAN tool to assess the credibility of subgroup findings (110). The GDG panel requested subgroup analyses based on: age (considering children vs younger adults vs older adults [70 years or older]); illness severity (non-severe vs severe vs critical COVID-19); time from onset of symptoms; and use of concomitant medications. However, there was insufficient within-trial data to perform any of these subgroup analyses, based on our pre-specified protocol. The panel recognized that usual care is likely variable between centres and regions, and has evolved over time. However, given all of the data come from RCTs, use of these co-interventions that comprise usual care should be balanced between study patients randomized to either the intervention or usual care arms. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ivermectin Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 0.19 (CI 95% 0.09 — 0.36) Based on data from 1419 participants in 7 studies. 1 (Randomized controlled) 70 per 1000 Difference: 14 per 1000 56 fewer per 1000 ( CI 95% 63 fewer — 44 fewer ) Very low Due to serious risk of bias and very serious imprecision 2 The effect of ivermectin on mortality is uncertain. Mechanical ventilation Odds ratio 0.51 (CI 95% 0.12 — 1.77) Based on data from 687 participants in 5 studies. (Randomized controlled) 20 per 1000 Difference: 10 per 1000 10 fewer per 1000 ( CI 95% 18 fewer Very low Due to very serious imprecision and publication bias 3 The effect of ivermectin on mechanical ventilation is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 97 of 142 — 15 more ) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Ivermectin Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Control arm of reference used for intervention. We elected to use the control arm of the WHO SOLIDARITY trial, reflecting usual care across countries participating in the trial. 2. Risk of bias: serious. The large trial contributing most of the effect estimate was driven by studies that were not blinded. Viral clearance 7 days Odds ratio 1.62 (CI 95% 0.95 — 2.86) Based on data from 625 participants in 6 studies. (Randomized controlled) 500 per 1000 Difference: 618 per 1000 118 more per 1000 ( CI 95% 13 fewer — 241 more ) Low Due to serious inconsistency and imprecision 4 Ivermectin may increase or have no effect on viral clearance. Hospital admission (outpatients only) Odds ratio 0.36 (CI 95% 0.08 — 1.48) Based on data from 398 participants in 1 study. (Randomized controlled) 50 per 1000 Difference: 18 per 1000 32 fewer per 1000 ( CI 95% 47 fewer — 23 more ) Very low Due to extremely serious imprecision 5 The effect of ivermectin on hospital admission is uncertain. Serious adverse events leading to discontinuation Odds ratio 3.07 (CI 95% 0.77 — 12.09) Based on data from 584 participants in 3 studies. (Randomized controlled) 9 per 1000 Difference: 27 per 1000 18 more per 1000 ( CI 95% 0 more — 89 more ) Low Due to very serious imprecision 6 Ivermectin may increase the risk of serious adverse events leading to drug discontinuation. Time to clinical improvement Measured by: days Lower better Based on data from 633 participants in 2 studies. (Randomized controlled) 11 days (Mean) Difference: 10.5 days (Mean) MD 0.5 fewer ( CI 95% 1.7 fewer — 1.1 more ) Low Due to very serious imprecision 7 Ivermectin may have little or no difference on time to clinical improvement. Duration of hospitalization Measured by: days Lower better Based on data from 252 participants in 3 studies. (Randomized controlled) 12.8 days (Mean) Difference: 11.7 days (Mean) MD 1.1 fewer ( CI 95% 2.3 fewer — 0.1 more ) Very low Due to serious imprecision, inconsistency and serious risk of bias 8 The effect of ivermectin on hospital length of stay is uncertain. Time to viral clearance Measured by: days Lower better Based on data from 559 participants in 4 studies. (Randomized controlled) 7.3 days (Mean) Difference: 5.7 days (Mean) MD 1.6 fewer ( CI 95% 4.1 fewer — 3 more ) Very low Due to very serious imprecision and serious risk of bias 9 We are uncertain whether ivermectin improves or worsens time to viral clearance. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 98 of 142 6.12.1 Mechanism of action Ivermectin is an antiparasitic agent that interferes with nerve and muscle function of helminths through binding glutamate-gated chloride channels (131). Based on in vitro experiments, some have postulated that ivermectin may have a direct antiviral effect against SARS-CoV-2. However, in humans the concentrations needed for in vitro inhibition are unlikely to be achieved by the doses proposed for COVID-19 (132)(133)(134). Ivermectin had no impact on SARS-CoV-2 viral RNA in the Syrian golden hamster model of SARS-CoV-2 infection (135). The proposed mechanism remains unclear: multiple targets have been proposed based upon either analogy to other viruses with very different life cycles, or, like several hundred other candidates, simulations indicating molecular docking with multiple viral targets including spike, RdRp and 3CLpro (136)(137)(138)(139)(140). No direct evidence for any mechanism of antiviral action against SARS-CoV-2 currently exists. Some have proposed, based predominantly upon research in other indications, that ivermectin has an immunomodulatory effect, but again the mechanism remains unclear. Historical data showed that ivermectin improved survival in mice given a lethal dose of lipopolysaccharide (141), and has benefits in murine models of atopic dermatitis and allergic asthma (142)(143). For SARS- CoV-2, one hypothesis suggests immunomodulation mediated by allosteric modulation of the alpha-7 nicotinic acetylcholine receptor (indirectly by modulating the activity of ligands of the receptor). Although investigators have demonstrated this action in vitro, concentrations used in these experiments have been even higher than those required for an antiviral effect (144), and therefore very unlikely to be achieved in humans. In the Syrian golden hamster model of SARS-CoV-2 infection, ivermectin resulted in some changes in pulmonary immune phenotype consistent with allosteric modulation of the alpha-7 nicotinic acetylcholine receptor (135). However, ivermectin did not appear to rescue body weight loss which is a hallmark of disease in this model, and drug concentrations were not measured to extrapolate to those achieved in humans. Taken together, there remains great uncertainty regarding the relevance of any immunomodulatory or anti-inflammatory action of ivermectin. 6.13 Hydroxychloroquine (published 17 December 2020) Imprecision: very serious. The number of total events was very small. 3. Imprecision: very serious. Very few events and credible intervals that include both important benefit and harm. Publication bias: serious. 4. Inconsistency: serious. The point estimates varied widely and credible intervals do not substantially overlap. Imprecision: serious. Credible interval includes no effect. 5. Imprecision: extremely serious. Credible interval includes important benefit and harm. 6. Imprecision: very serious. Credible interval includes little to no difference. 7. Imprecision: very serious. 8. Risk of bias: serious. Result driven by one study that was not blinded. Inconsistency: serious. Despite overlapping confidence intervals, point estimates discrepant. Imprecision: serious. Credible intervals include no difference. 9. Risk of bias: serious. Concerns around risk of bias. Imprecision: very serious. Credible interval includes important benefit and important harm. Info Box The recommendation concerning hydroxychloroquine was published 17 December 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLIDARITY trial on 15 October 2020, reporting results on treatment with hydroxychloroquine, remdesivir and lopinavir/ritonavir in hospitalized patients with COVID-19 (15). No changes were made to the hydroxychloroquine recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 99 of 142 For patients with COVID-19, regardless of disease severity Practical Info The GDG made a strong recommendation against using hydroxychloroquine or chloroquine for treatment of patients with COVID-19. The use of hydroxychloroquine may preclude the use of other important drugs that also prolong the QT interval, such as azithromycin and fluoroquinolones. Concomitant use of drugs that prolong the QT interval should be done with extreme caution. Evidence To Decision Strong recommendation against We recommend not to use hydroxychloroquine or chloroquine (strong recommendation against). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. Hydroxychloroquine and chloroquine probably do not reduce mortality or mechanical ventilation and may not reduce duration of hospitalization. The evidence does not exclude the potential for a small increased risk of death and mechanical ventilation with hydroxychloroquine. The effect on other less important outcomes, including time to symptom resolution, admission to hospital, and duration of mechanical ventilation, remains uncertain. Hydroxychloroquine may increase the risk of diarrhoea and nausea/vomiting; a finding consistent with evidence from its use in other conditions. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension and acute kidney injury, especially in settings where health care resources are limited. Whether or not and to what degree hydroxychloroquine increases the risk of cardiac toxicity, including life-threatening arrhythmias, is uncertain. Subgroup analyses indicated no effect modification based on severity of illness (comparing either critical vs severe/non- severe or non-severe vs critical/severe) or age (comparing those aged < 70 years vs older). Further, the cumulative dose and predicted Day 3 serum trough concentrations did not modify the effect for any outcome. Therefore, we assumed similar effects in all subgroups. We also reviewed evidence comparing the use of hydroxychloroquine plus azithromycin vs hydroxychloroquine alone. There was no evidence that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome (very low certainty). Benefits and harms For the key outcomes of mortality and mechanical ventilation, the panel considered the evidence to be of moderate certainty. There were residual concerns about lack of blinding in the largest trials and the imprecision. For example, the credible interval around the pooled effect leaves open the possibility of a very small reduction in mortality. The quality of evidence was low for diarrhoea and nausea/vomiting because of lack of blinding in many of the trials and because the total number of patients enrolled in trials reporting these outcomes was smaller than the optimal information size (although the credible interval laid entirely on the side of harm for both outcomes). For all other outcomes, the certainty of the evidence was low or very low. The primary concerns with the data were imprecision (credible intervals included both important benefit and important harm) as well as risk of bias (lack of blinding). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would not want to receive hydroxychloroquine given the evidence suggesting there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and vomiting. The panel did not expect there would be much variation in values and preferences between patients when it came to this intervention. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 100 of 142 Justification When moving from evidence to the strong recommendation against the use of hydroxychloroquine or chloroquine for patients with COVID-19, the panel emphasized the moderate certainty evidence of probably no reduction in mortality or need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased nausea and diarrhoea. The GDG did not anticipate important variability in patient values and preferences, and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity (see summary of these factors under Evidence to decision). Subgroup analyses The panel did not find any evidence of a subgroup effect across patients with different levels of disease severity, between adults and older adults, and by different doses, and therefore did not make any subgroup recommendation for this drug. In other words, the strong recommendation is applicable across disease severity, age groups, and all doses and dose schedules of hydroxychloroquine. The trials included patients from around the world, with all disease severities, and treated in different settings (outpatient and inpatient). Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease course. The GDG panel therefore felt that the evidence applies to all patients with COVID-19. Applicability Special populations None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with hydroxychloroquine. There were similar considerations in regards to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. Hydroxychloroquine crosses the placental barrier and there are concerns that it may lead to retinal damage in neonates. Although hydroxychloroquine has been used in pregnant women with systemic autoimmune diseases, such as systemic lupus erythematosus, pregnant women may have even more reasons than other patients to be reluctant to use hydroxychloroquine for COVID-19. In combination with azithromycin There was no evidence from the NMA that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome. As there were no trial data suggesting that azithromycin favourably modifies the effect of hydroxychloroquine, the recommendation against hydroxychloroquine and chloroquine applies to patients whether or not they are concomitantly receiving azithromycin. Uncertainties Please see end of document for residual uncertainties (Section 9). The GDG panel felt that it was unlikely future studies would identify a subgroup of patients that are likely to benefit from hydroxychloroquine or chloroquine. Hydroxychloroquine and chloroquine are relatively inexpensive compared with other drugs used for COVID-19 and are already widely available, including in low-income settings. Despite this, the panel felt that almost all patients would choose not to use hydroxychloroquine or chloroquine because the harms outweigh the benefits. Although the cost may be low per patient, the GDG panel raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe COVID-19 and other supportive care interventions. Resources and other considerations Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Hydroxychloroquine Comparator: Standard care Summary Evidence summary Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 101 of 142 The LNMA on hydroxychloroquine was based on 30 RCTs with 10 921 participants, providing relative estimates of effect for patient-important outcomes (see Table). Five of the trials (414 total participants) randomized some patients to chloroquine. The GRADE Summary of Findings table shows the relative and absolute effects of hydroxychloroquine compared with usual care for the outcomes of interest in patients with COVID-19, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis For hydroxychloroquine, the GDG panel requested subgroup analyses based on age (considering children vs younger adults [e.g. < 70 years] vs older adults [e.g. 70 years or older]), illness severity (non-severe vs severe vs critical COVID-19) and based on whether or not it was co-administered with azithromycin. The panel also requested a subgroup analysis based on high dose vs low dose hydroxychloroquine. A categorical approach to hydroxychloroquine dosing proved impossible because the trials used varying loading doses, continuation doses and durations. Therefore, in collaboration with a pharmacology expert (Professor Andrew Owen), we modelled the expected serum concentrations over time. We hypothesized that higher trough concentrations early in the treatment course (e.g. trough concentration on Day 3) might be more effective than lower early trough concentrations. We also hypothesized that higher maximum serum concentrations (e.g. peak concentration on the last day) might result in higher risk of adverse effects than lower maximum serum concentrations. In our pharmacokinetic model, the cumulative dose was highly correlated with all measures of serum concentrations on Day 3 and the final day of treatment, and therefore we decided to use cumulative dose as the primary analysis. Day 3 trough concentration was least strongly correlated with total cumulative dose (R2 = 0.376) and therefore we performed a sensitivity subgroup analysis with predicted Day 3 trough concentrations for efficacy outcomes. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 1.11 (CI 95% 0.95 — 1.31) Based on data from 10 859 participants in 29 studies. 1 (Randomized controlled) 106 per 1000 Difference: 116 per 1000 10 more per 1000 ( CI 95% 5 fewer — 28 more ) Moderate Due to borderline risk of bias and imprecision 2 Hydroxychloroquine probably does not reduce mortality. Mechanical ventilation Odds ratio 1.2 (CI 95% 0.83 — 1.81) Based on data from 6379 participants in 5 studies. (Randomized controlled) 105 per 1000 Difference: 123 per 1000 18 more per 1000 ( CI 95% 16 fewer — 70 more ) Moderate Due to borderline risk of bias and serious imprecision 3 Hydroxychloroquine probably does not reduce mechanical ventilation. Viral clearance 7 days Odds ratio 1.08 (CI 95% 0.25 — 4.78) Based on data from 280 participants in 4 studies. 4 (Randomized controlled) 483 per 1000 Difference: 502 per 1000 19 more per 1000 ( CI 95% 294 fewer — 334 more ) Very low Due to very serious imprecision 5 The effect of hydroxychloroquine on viral clearance is very uncertain. Admission to hospital Odds ratio 0.39 (CI 95% 0.12 — 1.28) Based on data from 465 participants in 1 study. (Randomized controlled) 47 per 1000 19 per 1000 Very low Due to very serious imprecision and serious indirectness 6 The effect of hydroxychloroquine on admission to hospital is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 102 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary ( CI 95% 41 fewer — 12 more ) Cardiac toxicity Based on data from 3287 participants in 7 studies. (Randomized controlled) 46 per 1000 Difference: 56 per 1000 10 more per 1000 ( CI 95% 0 more — 30 more ) Very low Due to serious imprecision, risk of bias, and indirectness 7 The effect of hydroxychloroquine on cardiac toxicity is uncertain. Diarrhoea Odds ratio 1.95 (CI 95% 1.4 — 2.73) Based on data from 979 participants in 6 studies. (Randomized controlled) 149 per 1000 Difference: 255 per 1000 106 more per 1000 ( CI 95% 48 more — 174 more ) Low Due to serious imprecision and risk of bias 8 Hydroxychloroquine may increase the risk of diarrhoea. Nausea/ vomiting Odds ratio 1.74 (CI 95% 1.26 — 2.41) Based on data from 1429 participants in 7 studies. (Randomized controlled) 99 per 1000 Difference: 161 per 1000 62 more per 1000 ( CI 95% 23 more — 110 more ) Low Due to serious imprecision and serious risk of bias 9 Hydroxychloroquine may increase the risk of nausea and vomiting. Delirium Odds ratio 1.59 (CI 95% 0.77 — 3.28) Based on data from 423 participants in 1 study. (Randomized controlled) 62 per 1000 Difference: 95 per 1000 33 more per 1000 ( CI 95% 14 fewer — 116 more ) Very low Due to very serious imprecision and serious indirectness 10 The effect of hydroxychloroquine on delirium is uncertain. Time to clinical improvement Lower better Based on data from 479 participants in 5 studies. (Randomized controlled) 11 days (Mean) Difference: 9 days (Mean) MD 2 fewer ( CI 95% 4 fewer — 0.1 more ) Very low Due to serious risk of bias, imprecision, and indirectness 11 The effect of hydroxychloroquine on time to clinical improvement is uncertain. Duration of hospitalization Lower better Based on data from 5534 participants in 5 studies. (Randomized controlled) 12.8 days (Mean) Difference: 12.9 days (Mean) MD 0.1 more ( CI 95% 1.9 fewer — 2 more ) Low Due to serious imprecision and serious risk of bias 12 Hydroxychloroquine may have no effect on duration of hospitalization. Time to viral clearance Lower better Based on data from 440 participants in 5 studies. (Randomized controlled) 9.7 days (Mean) 10.6 days (Mean) Very low Due to serious risk of bias and very serious imprecision 13 The effect of hydroxychloroquine on time to viral clearance is uncertain. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 103 of 142 Difference: 28 fewer per 1000 6.14 Lopinavir-ritonavir (published 17 December 2020) Outcome Timeframe Study results and measurements Comparator Standard care Intervention Hydroxychloro quine Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Primary study. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19. 2. Imprecision: serious. The 95% CI crosses the minimally important difference (2% reduction in mortality). . 3. Imprecision: serious. Wide confidence intervals. 4. Systematic review. We used the median event rate for all patients randomized to usual care across included studies. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [1], 5. Imprecision: very serious. Wide confidence intervals. 6. Indirectness: serious. Imprecision: very serious. 7. Risk of bias: serious. Unblinded studies -> cardiac toxicity differential detection. Indirectness: serious. Studies measured serious cardiac toxicity differently. Imprecision: serious. 8. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. OIS not met. Upgrade: large magnitude of effect. 9. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. OIS not met. Upgrade: large magnitude of effect. 10. Indirectness: serious. This outcome was not collected systematically and the definition of delirium was not specified. Imprecision: very serious. 11. Risk of bias: serious. Indirectness: serious. Studies measured clinical improvement differently. Imprecision: serious. 12. Risk of bias: serious. Imprecision: serious. Wide confidence intervals. 13. Risk of bias: serious. Imprecision: very serious. 14. Imprecision: extremely serious. fewer — 4.8 more ) Adverse events leading to drug discontinuation Based on data from 210 participants in 3 studies. (Randomized controlled) Two of 108 patients randomized to hydroxychloroquine discontinued treatment because of adverse effects. None of 102 patients did so in the placebo/standard care group. Very low Due to extremely serious imprecision 14 The effect of hydroxychloroquine on adverse events leading to drug discontinuation is uncertain. Info Box The recommendation concerning lopinavir-ritonavir was published 17 December 2020 as the third version of the WHO living guideline and in the BMJ as Rapid Recommendations. It followed the pre-print publication of the WHO SOLIDARITY trial on 15 October 2020, reporting results on treatment with lopinavir-ritonavirsivir, remdesivir and hydroxychloroquine in hospitalized patients with COVID-19 (15). No changes were made to the lopinavir-ritonavir recommendation in this eleventh version of the guideline. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 104 of 142 Difference: MD 0.7 fewer ( CI 95% 4.3 For patients with COVID-19, regardless of disease severity Evidence To Decision Justification When moving from evidence to the strong recommendation against the use of lopinavir-ritonavir for patients with COVID-19, the panel emphasized the moderate certainty evidence of probably no reduction in mortality or need for mechanical ventilation. It also noted the evidence suggesting possible harm associated with treatment, with increased nausea and diarrhoea. The GDG did not anticipate important variability in patient values and preferences, and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity would not alter the recommendation (see summary of these factors under Evidence to Decision). Strong recommendation against We recommend not to use lopinavir-ritonavir (strong recommendation against). Remark: This recommendation applies to patients with any disease severity and any duration of symptoms. The GDG panel found a lack of evidence that lopinavir-ritonavir improved outcomes that matter to patients such as reduced mortality, need for mechanical ventilation, time to clinical improvement and others. For mortality and need for mechanical ventilation this was based on moderate certainty evidence, for the other outcomes low or very low certainty evidence. There was low certainty evidence that lopinavir-ritonavir may increase the risk of diarrhoea and nausea and vomiting, a finding consistent with the indirect evidence evaluating its use in patients with HIV. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension and acute kidney injury, especially in settings where health care resources are limited. There was an uncertain effect on viral clearance and acute kidney injury. Subgroup analysis indicated no effect modification based on severity of illness (comparing either critical vs severe/non- severe or non-severe vs critical/severe) or age (comparing those aged < 70 years versus those 70 years and older). As there was no evidence of a statistical subgroup effect, we did not formally evaluate using the ICEMAN tool. Benefits and harms The evidence is based on a linked systematic review and NMA of seven RCTs; pooling data from 7429 patients hospitalized with various severities of COVID-19 and variably reporting the outcomes of interest to the guideline panel (1). The panel agreed that there was moderate certainty for mortality and need for mechanical ventilation, low certainty for diarrhoea, nausea and duration of hospitalization and very low certainty in the estimates of effect for viral clearance, acute kidney injury and time to clinical improvement. Most outcomes were lowered for risk of bias and imprecision (wide confidence intervals which do not exclude important benefit or harm). Certainty of the Evidence Applying the agreed values and preferences (see Section 7), the GDG inferred that almost all well-informed patients would not want to receive lopinavir-ritonavir given the evidence suggested there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea and vomiting. The panel did not expect there would be much variation in values and preferences between patients when it came to this intervention. Values and preferences Although the cost of lopinavir-ritonavir is not as high as some other investigational drugs for COVID-19, and the drug is generally available in most health care settings, the GDG raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe COVID-19. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 105 of 142 Subgroup analysis The panel did not find any evidence of a subgroup effect across patients with different levels of disease severity, or between adults and older adults and therefore did not make any subgroup recommendation for this drug. Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease course. The strong recommendation is applicable across disease severity and age groups. Applicability None of the included RCTs enrolled children, and therefore the applicability of this recommendation to children is currently uncertain. However, the panel had no reason to think that children with COVID-19 would respond any differently to treatment with lopinavir-ritonavir. There were similar considerations in regards to pregnant women, with no data directly examining this population, but no rationale to suggest they would respond differently than other adults. In patients using lopinavir-ritonavir for HIV infection, it should generally be continued while receiving care for COVID-19. Uncertainties Please see end of document for residual uncertainties (Section 9). The GDG panel felt that it was unlikely future studies would identify a subgroup of patients that are likely to benefit from lopinavir-ritonavir. Additional considerations In patients who have undiagnosed or untreated HIV, use of lopinavir-ritonavir alone may promote HIV resistance to important antiretrovirals. Widespread use of lopinavir-ritonavir for COVID-19 may cause drug shortages for people living with HIV. Clinical Question/ PICO Population: Patients with COVID-19 (all disease severities) Intervention: Lopinavir-ritonavir Comparator: Standard care Summary Evidence summary The LNMA on lopinavir-ritonavir was based on 7 RCTs with 7429 participants. Of note, none of the included studies enrolled children or adolescents under the age of 19 years old (see Table). The GRADE Summary of Findings table shows the relative and absolute effects of lopinavir-ritonavir compared with usual care for the outcomes of interest in patients with COVID-19 across all disease severities, with certainty ratings. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. Subgroup analysis For lopinavir-ritonavir, the GDG panel requested subgroup analyses based on age (considering children vs younger adults [e.g. under 70 years] vs older adults [e.g. 70 years or older]), and illness severity (non-severe vs severe vs critical COVID-19). The GDG discussed other potential subgroups of interest including time from onset of symptoms until initiation of therapy and concomitant medications, but recognized that these analyses would not be possible without access to individual participant data and/or more detailed reporting from the individual trials. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mortality Odds ratio 1 (CI 95% 0.82 — 1.2) Based on data from 8061 participants in 4 studies. 1 (Randomized controlled) 106 per 1000 Difference: 106 per 1000 0 fewer per 1000 ( CI 95% 17 fewer — 19 more ) Moderate Due to borderline risk of bias and imprecision 2 Lopinavir-ritonavir probably has no effect on mortality. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 106 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary Mechanical ventilation Relative risk 1.16 (CI 95% 0.98 — 1.36) Based on data from 7579 participants in 3 studies. (Randomized controlled) 105 per 1000 Difference: 122 per 1000 17 more per 1000 ( CI 95% 2 fewer — 38 more ) Moderate Due to borderline risk of bias and imprecision 3 Lopinavir-ritonavir probably does not reduce mechanical ventilation. Viral clearance Odds ratio 0.35 (CI 95% 0.04 — 1.97) Based on data from 171 participants in 2 studies. 4 (Randomized controlled) 483 per 1000 Difference: 246 per 1000 237 fewer per 1000 ( CI 95% 447 fewer — 165 more ) Low Due to very serious imprecision 5 The effects of lopinavir- ritonavir on viral clearance is very uncertain. Acute kidney injury Based on data from 259 participants in 2 studies. (Randomized controlled) 45 per 1000 Difference: 25 per 1000 20 fewer per 1000 ( CI 95% 70 fewer — 20 more ) Very low Due to serious risk of bias and very serious imprecision 6 The effect of lopinavir- ritonavir on acute kidney injury is uncertain. Diarrhoea Odds ratio 4.28 (CI 95% 1.99 — 9.18) Based on data from 370 participants in 4 studies. (Randomized controlled) 67 per 1000 Difference: 235 per 1000 168 more per 1000 ( CI 95% 58 more — 330 more ) Moderate Due to serious risk of bias and imprecision; upgraded due to large magnitude of effect 7 Lopinavir-ritonavir may increase the risk of diarrhoea. Nausea/ vomiting Based on data from 370 participants in 4 studies. (Randomized controlled) 17 per 1000 Difference: 177 per 1000 160 more per 1000 ( CI 95% 100 more — 210 more ) Moderate Due to serious risk of bias and imprecision 8 Lopinavir-ritonavir may increase the risk of nausea/vomiting. Time to clinical improvement Lower better Based on data from 199 participants in 1 study. (Randomized controlled) 11 days (Mean) Difference: 10 days (Mean) MD 1 fewer ( CI 95% 4.1 fewer — 3.2 more ) Very low Due to serious risk of bias and very serious imprecision 9 The effect of lopinavir- ritonavir improves on time to clinical improvement is very uncertain. Duration of hospitalization Lower better Based on data from 5239 participants in 2 12.8 days (Mean) 12.5 days (Mean) Low Due to serious risk of bias and imprecision 10 Lopinavir-ritonavir may have no effect on duration of hospitalization. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 107 of 142 6.15 Systemic corticosteroids (published 2 September 2020) For patients with severe or critical COVID-19 Practical Info Route: Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioavailability of dexamethasone is very high (that is, similar concentrations are achieved in plasma after oral and intravenous intake), critically ill patients may be unable to absorb any nutrients or medications due to intestinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Lopinavir- ritonavir Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review. Baseline/comparator: Primary study[15]. Baseline risk for mortality and mechanical ventilation were derived from the WHO SOLIDARITY trial for patients with severe and critical COVID-19. Supporting references: [1], 2. Imprecision: serious. The 95% CI crosses the minimally important difference (2% reduction in mortality). 3. Imprecision: serious. Wide confidence intervals. 4. Systematic review. Baseline/comparator: Control arm of reference used for intervention. We used the median event rate for all patients randomized to usual care across included studies. Supporting references: [1], 5. Imprecision: very serious. Wide confidence intervals. 6. Risk of bias: serious. Imprecision: very serious. Wide confidence intervals. 7. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. Few patients and events. Upgrade: large magnitude of effect. 8. Risk of bias: serious. Concerns mitigated because of large effect and indirect evidence showing consistent results. Imprecision: serious. Few patients and events. Upgrade: large magnitude of effect. 9. Risk of bias: serious. Imprecision: very serious. Wide confidence intervals, low number of patients. 10. Risk of bias: serious. Imprecision: serious. Wide confidence intervals. studies. (Randomized controlled) Difference: MD 0.3 lower ( CI 95% 3 lower — 2.5 higher ) Info Box The recommendations for corticosteroids were first published as WHO living guidelines 2 September 2020, and as BMJ Rapid Recommendations 5 September 2020. It followed the publication of the preliminary report of the RECOVERY trial, later published as a peer-reviewed paper (14). No changes were made to the corticosteroids recommendations in this eleventh version of the guideline. Whereas the recommendations remain unchanged, the evidence summary for corticosteroids in patients with COVID-19 was updated before the sixth iteration of this living guideline. The baseline risk estimates for mortality are now based on the WHO SOLIDARITY trial (as for other drugs in this guideline) (15) rather than the initial ISARIC cohort study (149) that likely overestimates current mortality risks at the global level. The update was also needed to inform the baseline risk for mortality in the evidence summary informing the strong recommendation for IL-6 receptor blockers, in addition to standard of care for patients with severe or critical COVID-19, where corticosteroids provide a relative reduction in mortality by 21%. Strong recommendation for We recommend treatment with systemic corticosteroids (strong recommendation for). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 108 of 142 Duration: While more patients received corticosteroids in the form of dexamethasone 6 mg daily for up to 10 days, the total duration of regimens evaluated in the seven trials varied between 5 and 14 days, and treatment was generally discontinued at hospital discharge (that is, the duration of treatment could be less than the duration stipulated in the protocols). Dose: The once daily dexamethasone formulation may increase adherence. A dose of 6 mg of dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg of hydrocortisone (that is, 50 mg every 8 hours), 40 mg of prednisone, or 32 mg of methylprednisolone (8 mg every 6 hours or 16 mg every 12 hours). Monitoring: It would be prudent to monitor glucose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to have diabetes. Timing: The timing of therapy from onset of symptoms was discussed by the panel. The RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 days or more after symptom onset may be more beneficial than treatment initiated within 7 days of symptom onset. A post hoc subgroup analysis within the PMA did not support this hypothesis. While some panel members believed that postponing systemic corticosteroids until after viral replication is contained by the immune system may be reasonable, many noted that, in practice, it is often impossible to ascertain symptom onset and that signs of severity often appear late (that is, denote a co-linearity between severity and timing). The panel concluded that, given the evidence, it was preferable to err on the side of administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 days of symptoms onset) and to err on the side of not giving corticosteroids when treating patients with non-severe disease (even if after 7 days of symptoms onset). Evidence To Decision Panel members who voted for a conditional recommendation argued that the trials evaluating systemic corticosteroids for COVID-19 reported limited information regarding potential harm. Between the two panel meetings, indirect evidence regarding the potential harmful effects of systemic corticosteroids from studies in sepsis, ARDS and community-acquired pneumonia (CAP) was added to the summary of findings table (150)(151). While generally of low certainty, these data were reassuring and suggested that corticosteroids are not associated with an increased risk of adverse events, beyond likely increasing the incidence of hyperglycaemia (moderate certainty evidence; absolute effect estimate 46 more per 1000 patients, 95% CI: 23 more to 72 more) and hypernatraemia (moderate certainty evidence; 26 more per 1000 patients, 95% CI: 13 more to 41 more). Panel members also noted that, given the expected effect of systemic corticosteroids on mortality, most patients would not refuse this intervention to avoid adverse events believed to be markedly less important to most patients than death. In contrast with new agents proposed for COVID-19, clinicians have a vast experience of systemic corticosteroids and the panel was reassured by their overall safety profile. Moreover, the panel was confident that clinicians using these guidelines would be aware of additional potential side-effects and contraindications to systemic corticosteroid therapy, which may vary geographically in function of endemic microbiological flora. Notwithstanding, clinicians should exercise caution in use of corticosteroids in patients with diabetes or underlying immunocompromise. Ultimately, the panel made its recommendation on the basis of the moderate certainty evidence of a 28-day mortality reduction of 8.7% in the critically ill and 6.7% in patients with severe COVID-19 who were not critically ill, respectively. In the fifth iteration of this living guideline, mortality baseline risk estimates were updated based on the WHO SOLIDARITY trial, considered to represent the best source of prognosis across countries facing the COVID-19 pandemic. This resulted in an overall 3.3% reduction in 28-day mortality for patients with severe or critical COVID-19, still with moderate certainty evidence and considered by the panel to represent a clear benefit to patients, with no impact on the established recommendations. Benefits and harms The panel took an individual patient perspective to values and preferences but, given the burden of the pandemic for health care systems globally, also placed a high value on resource allocation and equity. The benefits of corticosteroids on mortality was deemed of critical importance to patients, with little or no anticipated variability in their preference to be offered treatment if severely ill from COVID-19. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 109 of 142 Justification This recommendation was achieved after a vote, which concerned the strength of the recommendation in favour of systemic corticosteroids. Of the 23 voting panel members, 19 (83%) voted in favour of a strong recommendation, and 4 (17%) voted in favour of a conditional recommendation. The reasons for the four cautionary votes, which were shared by some panel members who voted in favour of a strong recommendation, are summarized below. Applicability Panel members who voted for a conditional recommendation argued that many patients who were potentially eligible for the RECOVERY trial were excluded from participating in the evaluation of corticosteroids by their treating clinicians and that without detailed information on the characteristics of excluded patients, this precluded, in their opinion, a strong recommendation. Other panel members felt that such a proportion of excluded patients was the norm rather than the exception in pragmatic trials and that, while detailed information on the reasons for excluding patients were not collected, the main reasons for refusing to offer participation in the trial were likely related to safety concerns of stopping corticosteroids in patients with a clear indication for corticosteroids (confirmed as per personal communication from the RECOVERY Principal Investigator). Panel members noted that there are few absolute contraindications to a 7–10 day course of corticosteroid therapy, that recommendations are intended for the average patient population, and that it is understood that even strong recommendations should not be applied to patients in whom the intervention is contraindicated as determined by the treating clinician. Eventually, the panel concluded that this recommendation applies to patients with severe and critical COVID-19 regardless of hospitalization status. The underlying assumption is that these patients would be treated in hospitals and receive respiratory support in the form of oxygen; non-invasive or invasive ventilation if these options were available. Following GRADE guidance, in making a strong recommendation, the panel has inferred that all or almost all fully informed patients with severe COVID-19 would choose to take systemic corticosteroids. It is understood that even in the context of a strong recommendation, the intervention may be contraindicated for certain patients. Absolute contraindications for 7–10 day courses of systemic corticosteroid therapy are rare. In considering potential contraindications, clinicians must determine if they warrant depriving a patient of a potentially life-saving therapy. The applicability of the recommendation is less clear for populations that were under-represented in the considered trials, such as children, patients with tuberculosis, and those who are immunocompromised. Notwithstanding, clinicians will also consider the risk of depriving these patients of potentially life-saving therapy. In contrast, the panel concluded that the recommendation should definitely be applied to certain patients who were not included in the trials, such as patients with severe and critical COVID-19 who could not be hospitalized or receive oxygen because of resource limitations. The recommendation does not apply to the following uses of corticosteroids: transdermal or inhaled administration, high-dose or long-term regimens, or prophylaxis. Resource implications, feasibility, equity and human rights In this guideline, the panel took an individual patient perspective, but also placed a high value on resource allocation. In such a perspective, attention is paid to the opportunity cost associated with the widespread provision of therapies for COVID-19. In contrast to other candidate treatments for COVID-19 that, generally, are expensive, often unlicensed, difficult to obtain and require advanced medical infrastructure, systemic corticosteroids are low cost, easy to administer, and readily available globally (152). Dexamethasone and prednisolone are among the most commonly listed medicines in national essential medicines lists; listed by 95% of countries. Dexamethasone was first listed by WHO as an essential medicine in 1977, while prednisolone was listed 2 years later (153). Accordingly, systemic corticosteroids are among a relatively small number of interventions for COVID-19 that have the potential to reduce inequities and improve equity in health. Those considerations influenced the strength of this recommendation. Acceptability The ease of administration, the relatively short duration of a course of systemic corticosteroid therapy, and the generally benign safety profile of systemic corticosteroids for up to 7–10 days led the panel to conclude that the acceptability of this intervention was high. Resources and other considerations Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 110 of 142 Clinical Question/ PICO Population: Patients with severe or critical COVID-19 (updated baseline mortality risk) Intervention: Systemic corticosteroids Comparator: Standard care Summary Evidence summary This guideline was triggered on 22 June 2020 by the publication of the preliminary report of the RECOVERY trial, later published as a peer-reviewed paper (14). Corticosteroids are listed in the WHO Model List of Essential Medicines, readily available globally at a low cost, and of considerable interest to all stakeholder groups. The guideline panel was informed by combining two meta-analyses which pooled data from eight randomized trials (7184 participants) of systemic corticosteroids for COVID-19 (1)(154). The panel discussions were also informed by two other meta-analyses, which were already published and pooled data about the safety of systemic corticosteroids in distinct but relevant patient populations. The GRADE Summary of Findings table shows the relative and absolute effects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with severe and critical COVID-19, with certainty ratings. Below we provide more details about the trials and meta-analysis as well as a subgroup analysis that informed the recommendation. See Section 7 for sources of baseline risk estimates informing absolute estimates of effect. On 17 July 2020, the panel reviewed evidence from eight RCTs (7184 patients) evaluating systemic corticosteroids versus usual care in COVID-19. RECOVERY, the largest of the seven trials, from which mortality data were available by subgroup (severe and non-severe), evaluated the effects of dexamethasone 6 mg given once daily (oral or intravenous) for up to 10 days in 6425 hospitalized patients in the United Kingdom (2104 were randomized to dexamethasone and 4321 were randomized to usual care) (14). At the time of randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; 60% were receiving oxygen only (with or without non-invasive ventilation); and 24% were receiving neither. The data from seven other smaller trials included 63 non-critically ill patients and approximately 700 critically ill patients (definitions of critical illness varied across studies). For the latter, patients were enrolled up to 9 June 2020, and approximately four-fifths were invasively mechanically ventilated; approximately half were randomized to receive corticosteroid therapy, and half randomized to no corticosteroid therapy. Corticosteroid regimens included: methylprednisolone 40 mg every 12 hours for 3 days and then 20 mg every 12 hours for 3 days (GLUCOCOVID) (155); dexamethasone 20 mg daily for 5 days followed by 10 mg daily for 5 days (two trials, DEXA-COVID19, CoDEX) (156)(157); hydrocortisone 200 mg daily for 4 to 7 days followed by 100 mg daily for 2 to 4 days and then 50 mg daily for 2 to 3 days (one trial, CAPE-COVID) (158); hydrocortisone 200 mg daily for 7 days (one trial, REMAP- CAP) (16); methylprednisolone 40 mg every 12 hours for 5 days (one trial, Steroids-SARI) (159). Seven of the trials were conducted in individual countries (Brazil, China, Denmark, France, Spain) whilst REMAP-CAP was an international study (recruiting in 14 European countries, Australia, Canada, New Zealand, Saudi Arabia and the United Kingdom). All trials reported mortality 28 days after randomization, except for one trial at 21 days and another at 30 days. Because the mortality data from one trial (GLUCOCOVID, n=63) were not reported by subgroup, the panel reviewed only the data pertaining to the outcome of mechanical ventilation from this trial (155). An additional trial, which randomized hospitalized patients with suspected SARS-CoV-2 infection, published on 12 August 2020 (MetCOVID) (160), was included as a supplement in the PMA publication, as it was registered after the searches of trial registries were performed. The supplement showed that inclusion would not change results other than reduce inconsistency. Subgroup analyses While all other trials evaluated systemic corticosteroids exclusively in critically ill patients, the RECOVERY trial enrolled hospitalized patients with COVID-19. The panel considered the results of a subgroup analysis of the RECOVERY trial suggesting that the relative effects of systemic corticosteroids varied as a function of the level of respiratory support received at randomization. On the basis of the peer-reviewed criteria for credible subgroup effects (110), the panel determined that the subgroup effect was sufficiently credible to warrant separate recommendations for severe and non- severe COVID-19. However, acknowledging that during a pandemic, access to health care may vary considerably over time as well as between different countries, the panel decided against defining patient populations concerned by the recommendations on the basis of access to health interventions (i.e. hospitalization and respiratory support). Thus, the panel attributed the effect modification in the RECOVERY trial to illness severity. The panel also acknowledged the existence of variable definitions for severity and use of respiratory support interventions. The WHO clinical guidance for COVID-19 published on 27 May 2020 (version 3) defined severity of COVID-19 by clinical indicators, but modified the oxygen saturation threshold from 94% to 90%, in order to align with Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 111 of 142 previous WHO guidance (6). See Section 5 for the WHO severity criteria and Infographic for three disease severity groups for which the recommendations apply in practice. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Relative risk 0.79 (CI 95% 0.7 — 0.9) Based on data from 1703 participants in 7 studies. 1 Follow up: 28 days. 160 per 1000 Difference: 126 per 1000 34 fewer per 1000 ( CI 95% 48 fewer — 16 fewer ) Moderate Due to serious risk of bias 2 Systemic corticosteroids probably reduce the risk of 28-day mortality in patients with critical illness due to COVID-19. Need for invasive mechanical ventilation 28 days Relative risk 0.74 (CI 95% 0.59 — 0.93) Based on data from 5481 participants in 2 studies. Follow up: 28 days. 116 per 1000 Difference: 86 per 1000 30 fewer per 1000 ( CI 95% 48 fewer — 8 fewer ) Moderate Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need of mechanical ventilation. Gastrointestinal bleeding Relative risk 1.06 (CI 95% 0.85 — 1.33) Based on data from 5403 participants in 30 studies. 48 per 1000 Difference: 51 per 1000 3 more per 1000 ( CI 95% 7 fewer — 16 more ) Low Due to serious indirectness, Due to serious imprecision 4 Corticosteroids may not increase the risk of gastrointestinal bleeding. Super-infections Relative risk 1.01 (CI 95% 0.9 — 1.13) Based on data from 6027 participants in 32 studies. 186 per 1000 Difference: 188 per 1000 2 more per 1000 ( CI 95% 19 fewer — 24 more ) Low Due to serious indirectness, Due to serious imprecision 5 Corticosteroids may not increase the risk of super-infections. Hyperglycaemia Relative risk 1.16 (CI 95% 1.08 — 1.25) Based on data from 8938 participants in 24 studies. 286 per 1000 Difference: 332 per 1000 46 more per 1000 ( CI 95% 23 more — 72 more ) Moderate Due to serious indirectness 6 Corticosteroids probably increase the risk of hyperglycaemia. Hypernatremia Relative risk 1.64 (CI 95% 1.32 — 2.03) Based on data from 5015 participants in 6 studies. 40 per 1000 Difference: 66 per 1000 26 more per 1000 ( CI 95% 13 more — 41 more ) Moderate Due to serious indirectness 7 Corticosteroids probably increase the risk of hypernatremia. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 112 of 142 For patients with non-severe COVID-19 infection Practical Info With the conditional recommendation against the use of corticosteroids in patients with non-severe COVID-19 the following practical information apply in situations where such treatment is to be considered: Route: Systemic corticosteroids may be administered both orally and intravenously. Of note, while the bioavailability of dexamethasone is very high (i.e. similar concentrations are achieved in plasma after oral and intravenous intake), critically ill patients may be unable to absorb any nutrients or medications due to intestinal dysfunction. Clinicians therefore may consider administering systemic corticosteroids intravenously rather than orally if intestinal dysfunction is suspected. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary 1. Systematic review [1] . Baseline/comparator: Primary study[15]. Baseline risk estimate for mortality updated as of May 2021: now from WHO SOLIDARITY (considered the best source) with 14.6% mortality at 28 days in severe and critically ill patients. This estimate adjusted for 50% receiving corticosteroids as standard of care in SOLIDARITY. 2. Risk of bias: serious. Lack of blinding. 3. Risk of bias: serious. Lack of blinding. 4. Indirectness: serious. Imprecision: serious. 5. Indirectness: serious. Imprecision: serious. 6. Indirectness: serious. 7. Indirectness: serious. 8. Indirectness: serious. Imprecision: serious. 9. Indirectness: serious. Imprecision: serious. 10. Risk of bias: serious. Lack of blinding. Imprecision: serious. Confidence interval includes no benefit. Neuromuscular weakness Relative risk 1.09 (CI 95% 0.86 — 1.39) Based on data from 6358 participants in 8 studies. 69 per 1000 Difference: 75 per 1000 6 more per 1000 ( CI 95% 10 fewer — 27 more ) Low Due to serious indirectness, Due to serious imprecision 8 Corticosteroids may not increase the risk of neuromuscular weakness. Neuropsychiatri c effects Relative risk 0.81 (CI 95% 0.41 — 1.63) Based on data from 1813 participants in 7 studies. 35 per 1000 Difference: 28 per 1000 7 fewer per 1000 ( CI 95% 21 fewer — 22 more ) Low Due to serious indirectness, Due to serious imprecision 9 Corticosteroids may not increase the risk of neuropsychiatric effects. Duration of hospitalization Measured by: days Lower better Based on data from 6425 participants in 1 study. (Randomized controlled) 13 days 12 days Low Due to serious risk of bias and serious imprecision 10 Steroids may result in an important reduction in the duration of hospitalizations. Conditional recommendation against We suggest not to use systemic corticosteroids (conditional recommendation against). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 113 of 142 Duration: While more patients received corticosteroids in the form of dexamethasone 6 mg daily for up to 10 days, the total duration of regimens evaluated in the seven trials varied between 5 and 14 days, and treatment was generally discontinued at hospital discharge (i.e. the duration of treatment could be less than the duration stipulated in the protocols). Dose: The once daily dexamethasone formulation may increase adherence. A dose of 6 mg of dexamethasone is equivalent (in terms of glucocorticoid effect) to 150 mg of hydrocortisone (e.g. 50 mg every 8 hours), or 40 mg of prednisone, or 32 mg of methylprednisolone (e.g. 8 mg every 6 hours or 16 mg every 12 hours). It would be prudent to monitor glucose levels in patients with severe and critical COVID-19, regardless of whether the patient is known to have diabetes. Timing: The timing of therapy from onset of symptoms was discussed by the panel. The RECOVERY investigators reported a subgroup analysis suggesting that the initiation of therapy 7 days or more after symptom onset may be more beneficial than treatment initiated within 7 days of treatment onset. A post hoc subgroup analysis within the PMA did not support this hypothesis. While some panel members believed that postponing systemic corticosteroids until after viral replication is contained by the immune system may be reasonable, many noted that, in practice, it is often impossible to ascertain symptom onset and that signs of severity frequently appear late (i.e. denote a co-linearity between severity and timing). The panel concluded that, given the evidence, it was preferable to err on the side of administering corticosteroids when treating patients with severe or critical COVID-19 (even if within 7 days of symptoms onset) and to err on the side of not giving corticosteroids when treating patients with non-severe disease (even if after 7 days of symptoms onset). Other endemic infections that may worsen with corticosteroids should be considered. For example, for Strongyloides stercoralis hyperinfection associated with corticosteroid therapy, diagnosis or empiric treatment may be considered in endemic areas if steroids are used. Evidence To Decision The panel made its recommendation on the basis of low certainty evidence suggesting a potential increase of 3.9% in 28-day mortality among patients with COVID-19 who are not severely ill. The certainty of the evidence for this specific subgroup was downgraded due to serious imprecision (i.e. the evidence does not allow to rule out a mortality reduction) and risk of bias due to lack of blinding. In making a conditional recommendation against the indiscriminate use of systemic corticosteroids, the panel inferred that most fully informed individuals with non-severe illness would not want to receive systemic corticosteroids, but many could want to consider this intervention through shared decision-making with their treating physician (161)(6). Note: WHO recommends antenatal corticosteroid therapy for pregnant women at risk of preterm birth from 24 to 34 weeks’ gestation when there is no clinical evidence of maternal infection, and adequate childbirth and newborn care is available. However, in cases where the woman presents with mild or moderate COVID-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman’s clinical condition, her wishes and that of her family, and available health care resources. Benefits and harms See Benefits and Harms section. Certainty of the Evidence The weak or conditional recommendation was driven by likely variation in patient values and preferences. The panel judged that most individuals with non-severe illness would decline systemic corticosteroids. However, many may want them after shared decision-making with their treating physician. Values and preferences Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 114 of 142 Justification This recommendation was achieved by consensus. Applicability This recommendation applies to patients with non-severe disease regardless of their hospitalization status. The panel noted that patients with non-severe COVID-19 would not normally require acute care in hospital or respiratory support, but that in some jurisdictions, these patients may be hospitalized for isolation purposes only, in which case they should not be treated with systemic corticosteroids. The panel concluded that systemic corticosteroids should not be stopped for patients with non-severe COVID-19 who are already treated with systemic corticosteroids for other reasons (e.g. patients with chronic obstructive pulmonary disease or other chronic autoimmune diseases need not discontinue a course of systemic oral corticosteroid). If the clinical condition of patients with non-severe COVID-19 worsens (i.e. increase in respiratory rate, signs of respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation for severe and critical COVID-19). Resource implications, feasibility, equity and human rights The panel also considered that in order to help guarantee access to systemic corticosteroids for patients with severe and critical COVID-19, it is reasonable to avoid administering this intervention to patients who, given the current evidence, would not appear to derive any benefit from this intervention. Resources and other considerations Clinical Question/ PICO Population: Patients with non-severe COVID-19 Intervention: Systemic corticosteroids Comparator: Standard care Summary Evidence summary Please see evidence summary above (placed under recommendation for patients with severe and critical COVID-19 to find more information about the eight RCTs pooled into two systematic reviews with meta-analysis. It also provides information about additional systematic reviews used to inform safety outcomes and results of subgroup analyses resulting in separate recommendations for patients with non-severe COVID-19 and those with severe and critical illness. The GRADE Summary of Findings table shows the relative and absolute effects of systemic corticosteroids compared with usual care for the outcomes of interest in patients with non-severe COVID-19, with certainty ratings. Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary Mortality 28 days Relative risk 1.22 (CI 95% 0.93 — 1.61) Based on data from 1535 participants in 1 study. 1 Follow up: 28 days. 23 per 1000 Difference: 28 per 1000 5 more per 1000 ( CI 95% 2 fewer — 14 more ) Low Due to serious risk of bias and serious imprecision 2 Systemic corticosteroids may increase the risk of 28-day mortality in patients with non-severe COVID-19. Need for invasive mechanical ventilation 28 days Relative risk 0.74 (CI 95% 0.59 — 0.93) Based on data from 5481 participants in 2 studies. Follow up: 28 days. 116 per 1000 86 per 1000 Moderate Due to serious risk of bias 3 Systemic corticosteroids probably reduce the need for mechanical ventilation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 115 of 142 Outcome Timeframe Study results and measurements Comparator Standard care Intervention Systemic corticosteroids Certainty of the Evidence (Quality of evidence) Plain language summary ( CI 95% 48 fewer — 8 fewer ) Gastrointestinal bleeding Relative risk 1.06 (CI 95% 0.85 — 1.33) Based on data from 5403 participants in 30 studies. 4 48 per 1000 Difference: 51 per 1000 3 more per 1000 ( CI 95% 7 fewer — 16 more ) Low Due to serious indirectness and serious imprecision 5 Corticosteroids may not increase the risk of gastrointestinal bleeding. Super-infections Relative risk 1.01 (CI 95% 0.9 — 1.13) Based on data from 6027 participants in 32 studies. 186 per 1000 Difference: 188 per 1000 2 more per 1000 ( CI 95% 19 fewer — 24 more ) Low Due to serious indirectness, Due to serious imprecision 6 Corticosteroids may not increase the risk of super-infections. Hyperglycaemia Relative risk 1.16 (CI 95% 1.08 — 1.25) Based on data from 8938 participants in 24 studies. 286 per 1000 Difference: 332 per 1000 46 more per 1000 ( CI 95% 23 more — 72 more ) Moderate Due to serious indirectness 7 Corticosteroids probably increase the risk of hyperglycaemia. Hypernatremia Relative risk 1.64 (CI 95% 1.32 — 2.03) Based on data from 5015 participants in 6 studies. 40 per 1000 Difference: 66 per 1000 26 more per 1000 ( CI 95% 13 more — 41 more ) Moderate Due to serious indirectness 8 Corticosteroids probably increase the risk of hypernatremia. Neuromuscular weakness Relative risk 1.09 (CI 95% 0.86 — 1.39) Based on data from 6358 participants in 8 studies. 69 per 1000 Difference: 75 per 1000 6 more per 1000 ( CI 95% 10 fewer — 27 more ) Low Due to serious indirectness and serious imprecision 9 Corticosteroids may not increase the risk of neuromuscular weakness. Neuropsychiatri c effects Relative risk 0.81 (CI 95% 0.41 — 1.63) Based on data from 1813 participants in 7 studies. 35 per 1000 Difference: 28 per 1000 7 fewer per 1000 ( CI 95% 21 fewer — 22 more ) Low Due to serious indirectness and serious imprecision 10 Corticosteroids may not increase the risk of neuropsychiatric effects. Duration of hospitalization 13 days 12 days Low Due to serious risk of bias and serious imprecision 11 Steroids may result in an important reduction in the duration of hospitalizations. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 116 of 142 Difference: 30 fewer per 1000 Measured by: days Lower better Based on data from 6425 participants in 1 study. (Randomized controlled) 1. Systematic review [1] . Baseline/comparator: Primary study[15]. We derived baseline risk for mortality and mechanical ventilation from the control arm of the WHO SOLIDARITY trial. 2. Risk of bias: serious. lack of blinding. Imprecision: serious. 3. Risk of bias: serious. lack of blinding. 4. Systematic review. Baseline/comparator: Control arm of reference used for intervention. Supporting references: [1], 5. Indirectness: serious. Imprecision: serious. 6. Indirectness: serious. Imprecision: serious. 7. Indirectness: serious. 8. Indirectness: serious. 9. Indirectness: serious. Imprecision: serious. 10. Indirectness: serious. Imprecision: serious. 11. Risk of bias: serious. lack of blinding. Imprecision: serious. confidence interval includes no benefit. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 117 of 142 7. Methods: how this guideline was created This living WHO 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) (161). Related guidelines This living WHO guideline for COVID-19 treatments is related to the larger, more comprehensive guidance for COVID-19 Clinical management: living guideline, which has a wider scope of content and has been regularly updated (6). The first ten versions of this WHO Therapeutics and COVID-19: living guideline, addressing corticosteroids, remdesivir, hydroxychloroquine, lopinavir/ritonavir, ivermectin, IL-6 receptor blockers, casirivimab-imdevimab (neutralizing monoclonal antibodies), convalescent plasma, JAK inhibitors, sotrovimab, molnupiravir, remdesivir and nirmatrelvir-ritonavir can be accessed via the WHO website (4). Guidelines regarding the use of drugs to prevent (rather than treat) COVID-19 are included in a separate document, WHO Living guideline: Drugs to prevent COVID-19, that can be accessed via the WHO website and the BMJ (8). Timing This guideline is living – dynamically updated and globally disseminated once new evidence warrants a change in recommendations (162). The aim is for a six-week timeframe from the public availability of trial data that trigger the guideline development process to WHO publication, while maintaining standards for trustworthy guidelines (WHO Handbook for guideline development) (161)(163). Stepwise approach Here we outline the approach, involving simultaneous processes, taken to improve efficiency and timeliness of development and dissemination of living, trustworthy guidance. Step 1: Evidence monitoring and mapping and triggering of evidence synthesis Comprehensive daily monitoring of all emerging RCTs occurs on a continuous basis, within the context of the living systematic review and network meta-analysis (NMA), using experienced information specialists, who review all relevant information sources for new RCTs addressing interventions for COVID-19. Incorporating pre-print data, which have not yet undergone peer review, promote rapid data sharing in a public health emergency and its inclusion can accelerate the assessment and clinical use of COVID-19 therapeutic interventions. Guidelines are periodically updated to assess data that have undergone peer review in the intervening period and new data. Once practice-changing evidence, or increasing international interest, are identified, the WHO Therapeutics Steering Committee triggers the guideline development process. The trigger for producing or updating specific recommendations is based on the following (any of the three may initiate a recommendation): • likelihood to change practice; • sufficient RCT data on therapeutics to inform the high-quality evidence synthesis living systematic review; • relevance to a global audience. Step 2: Convening the GDG WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise, and patient representatives. For each intervention, the technical unit collected and managed declarations of interests (DOIs) and found no GDG member and co-chairs to have a conflict of interest. In addition to the distribution of a DOI form, during the meeting, the WHO Secretariat described the DOI process and an opportunity was given to GDG members to declare any interests not provided in written form. No verbal conflicts were declared. Web searches did not identify any additional interests that could be perceived to affect an individual’s objectivity and independence during the development of the recommendations. The pre-selected expert GDG (see Section 10) convened on 07 April 2022 to address fluvoxamine and colchicine. The meeting involved a review of the basics of GRADE methodology including formulating population, intervention, comparator, outcome (PICO) questions and subgroups of interests, and prioritization of patient-important outcomes (see step 4 below). The GDG subsequently reviewed analyses, including pre-specified subgroup analyses presented in summary of findings tables, considered an individual patient perspective and feasibility issues specific to this intervention, and formulated recommendations. The GDG also reviewed the mechanism of actions and non-clinical evidence around safety. Step 3: Evidence synthesis The living systematic review/NMA team, as requested by the WHO Therapeutics Steering Committee, performed an independent systematic review to examine the benefits and harms of the interventions (1). The systematic review team includes systematic review experts, clinical experts, clinical epidemiologists and biostatisticians. Team members have expertise in GRADE methodology and rating certainty of evidence specifically in NMAs, including direct and indirect comparisons of treatment alternatives. The NMA team Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 118 of 142 considered deliberations from the initial GDG meeting, specifically focusing on the outcomes and subgroups prioritized by the GDG and produced GRADE evidence summaries to inform development of recommendations. In situations where no head-to-head comparisons of therapeutics were available from RCTs, the LNMA team performed indirect comparisons and produced additional GRADE evidence summaries that the GDG used to inform recommendations. The methods team rated credibility of subgroups using the ICEMAN tool (110). The technical unit collected and managed declarations of interests (DOIs) and found no SR team member to have a conflict of interest. Step 4: Final recommendations The GRADE approach provided the framework for establishing evidence certainty and generating both the direction and strength of recommendations (164)(165). A priori voting rules informed procedures if the GDG failed to reach consensus. There was no need for voting. The following key factors informed transparent and trustworthy recommendations: • absolute benefits and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE summary of findings tables) (166); • quality/certainty of the evidence (164)(167); • values and preferences of patients (168); • resources and other considerations (including considerations of feasibility, applicability, equity) (168); • effect estimates and confidence intervals for each outcome, with an associated rating of certainty in the evidence, as presented in summary of findings tables. If such data are not available, the GDG reviews narrative summaries (166); • recommendations are rated as either conditional or strong, as defined by GRADE. If the GDG members disagree regarding the evidence assessment or strength of recommendations, WHO will apply voting according to established rules (165)(168). When possible, we used research evidence to inform discussion around these key factors. If not available, discussion of these factors was informed by expert opinion, supported by surveys of the GDG members as outlined below. Benefits and harms The GDG members prioritized outcomes (rating from 9 [critical] to 1 [not important] ) in patients with non-severe COVID-19 and in patients with severe and critical COVID-19, taking a patient perspective (Tables 1 and 2 below). The GDG's questions were structured using the PICO format (see evidence profile under the recommendations). The prioritization was performed through a survey, most lately in May 2021, followed by a GDG discussion. These prioritized outcomes were used to update the LNMA (2). Selecting and rating the importance of outcomes GDG members prioritized outcomes from the perspective of patients with non-severe illness (Table 1) and severe and critical illness (Table 2). Table 1. GDG outcome rating from the perspective of patients with non-severe illness Outcome Mean SD Range Admission to hospital 8.5 0.7 7-9 Death 8.1 1.9 3-9 Quality of life 7.5 1.3 5-9 Serious adverse effects (e.g. adverse events leading to drug discontinuation) 7.4 1.8 3-9 Time to symptom resolution 7.3 1.7 4-9 Duration of hospitalization 6.6 0.9 5-8 Duration of oxygen support 6.6 1.2 5-9 Need for invasive mechanical ventilation 5.9 2.3 1-8 New non-SARS-CoV-2 infection 5.6 2.1 3-9 Time to viral clearance 5.5 2.4 1-9 Duration of invasive mechanical ventilation 5.4 2.1 1-8 SD: standard deviation. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 119 of 142 Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. Table 2. GDG outcome rating from the perspective of patients with severe and critical illness Outcome Mean SD Range Death 9.0 0 9 Need for invasive mechanical ventilation 8.2 0.9 6-9 Duration of invasive mechanical ventilation 7.6 0.9 6-9 Quality of life 6.9 1.3 5-9 Duration of hospitalization 6.7 1.2 4-9 Serious adverse effects (e.g. adverse events leading to drug discontinuation) 6.7 1.8 3-9 Time to symptom resolution 6.5 1.6 4-9 New non-SARS-CoV-2 infection 6.4 1.8 3-9 Duration of oxygen support 6.3 1.3 4-9 Time to viral clearance 4.7 2.3 1-9 SD: standard deviation. Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. Derivation of absolute effects for drug treatments For patients with non-severe illness, we used the median of the control arm of the RCTs that contributed to the evidence, identified in the LNMA (1)(2) . For admission to hospital, the GDG defined a 10% (100 admissions per 1000 patients) threshold for a baseline risk that would reflect an important absolute benefit for the therapeutics under consideration (i.e., 60 fewer admissions per 1000 patients). For patients with severe and critical illness, the GDG identified the control arm of the WHO SOLIDARITY trial, performed across a wide variety of countries and geographical regions, as representing the most relevant source of evidence for baseline risk estimates for mortality and mechanical ventilation. Systemic corticosteroids now represent standard of care in patients with severe and critical COVID-19 (see strong recommendation issued by WHO September 2020). Therefore, the baseline risk estimates in the evidence summaries for JAK inhibitors, convalescent plasma and IL-6 receptor blockers were adjusted for treatment effects of corticosteroids for the outcome of mortality and mechanical ventilation. The applied baseline risk estimate for mortality was 13% (130 deaths per 1000 patients). For other outcomes, we used the median of the control arm of the RCTs that contributed to the evidence. Specific deliberations on baseline risk are presented for each recommendation. The GDG acknowledged that baseline risks, and thus absolute effects, may vary significantly geographically and over time. Thus, users of this guideline may prefer estimating absolute effects by using local event rates. Values and preferences We had insufficient information to provide the GDG with an evidence-based description of patient experiences or values and preferences regarding treatment decisions for COVID-19 drug treatments. The GDG, therefore, relied on their own judgments of what well-informed patients would value after carefully balancing the benefits, harms, and burdens of treatment. Judgments on values and preferences were crucially informed through the experiences of former COVID-19 patients, represented in the GDG. The GDG agreed that the following values and preferences would be typical of well-informed patients: • Most patients would be reluctant to use a medication for which the evidence left high uncertainty regarding effects on outcomes they consider important. This was particularly so when evidence suggested treatment effects, if they do exist, are small, and the possibility of important harm remains. • In an alternative situation with larger benefits and less uncertainty regarding both benefits and harms, more patients would be inclined to choose the intervention. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 120 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) acceptability, equity and cost were important considerations. Specific deliberations on values and preferences and associated feasibility and resource related considerations are presented for each recommendation. Step 5: External and internal review An external review group reviewed the final guideline document to identify factual errors, and to comment on clarity of language, contextual issues and implications for implementation. The technical unit collected and managed declarations of interests (DOIs) of the external reviewers and found no external reviewer to have a conflict of interest. However, for certain therapeutics, pharmaceutical company technical representative may be asked to comment on a new drug from the industry perspectives, in line with the WHO Handbook (page 70), as comments from such individuals or organizations on a draft guideline may be helpful in anticipating and dealing with controversy, identifying factual errors, and promoting engagement with all stakeholders. Comments on contextual issues were considered taking into account their interests. The conflict of interest of such individuals will be transparent, as their affiliation will appear in the acknowledgement section. The guideline was then reviewed and approved by the WHO GRC and the Publication Review Committee. 121 of 142 In addition to taking an individual patient perspective, the GDG also considered a population perspective in which feasibility, 8. How to access and use this guideline This is a living guideline from WHO. The recommendations included here will be updated, and new recommendations will be added for other drugs for COVID-19. How to access the guideline: • WHO website in PDF format (4): This is a full read out of the MAGICapp content for those without reliable web access. It can also be downloaded directly from MAGICapp (see cogwheel on top right). • MAGICapp in online, multilayered formats: This is the fullest version of the guideline, as detailed below. • BMJ Rapid Recommendations (5): Designed with clinical readers in mind and including an interactive infographic to summarize all treatments included. • WHO Academy app: Mobile application available for health workers and public on Apple Store and Google Play with a full Case Management section which includes Guidance, Training and Tools, including the latest training modules on Therapeutics for COVID-19. Includes treatment and other guidelines and training materials from WHO on COVID-19 for use offline. • WHO COVID-19 Clinical Care Pathway is a new tool that summarizes these recommendations in a concise and easy to understand manner for health workers. It links this guideline to WHO guidelines on Diagnostic testing for SARS-CoV-2 and Antigen-detection in the diagnosis of SARS-CoV-2 infection to aid in implementation. How to navigate this guideline The guideline is written, disseminated, and updated in MAGICapp, with a format and structure that ensures user-friendliness and ease of navigation (163). It accommodates dynamic updating of evidence and recommendations that can focus on what is new while keeping existing recommendations, as appropriate, within the guideline. The purpose of the online formats and additional tools, such as the infographics, is to make it easier to navigate and make use of the guideline in busy clinical practice. The online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting evidence and other information pertinent to applying the recommendations in practice, including tools for shared decision-making (clinical encounter decision aids) (163). Fig. 4 shows how the online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting information pertinent to applying the recommendations in practice. End-users will also need to understand what is meant by strong and conditional recommendations (displayed immediately below) and certainty of evidence (the extent to which the estimates of effect from research represent true effects from treatment). For each recommendation additional information is available through the following tabs: • Research evidence: Readers can find details about the research evidence underpinning the recommendations as GRADE Summary of Findings tables and narrative evidence summaries (shown in Fig. 4). • Evidence to decision: The absolute benefits and harms are summarized, along with other factors such as the values and preferences of patients, practical issues around delivering the treatment as well as considerations concerning resources, applicability, feasibility, equity and human rights. These latter factors are particularly important for those in need of adapting the guidelines for the national or local context. • Justification: Explanation of how the GDG considered and integrated evidence to decision factors when creating the recommendations, focussing on controversial and challenging issues. • Practical information: For example, dosing, duration and administration of drugs, or how to apply tests to identify patients in practice. • Decision aids: Tools for shared decision-making in clinical encounters. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 122 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 123 of 142 Fig. 4. Example of how research evidence is available one click away, with narrative evidence summary giving additional details to GRADE Summary of Findings table This living guideline from WHO is also used to inform the activities of the WHO Prequalification of Medicinal Products. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 124 of 142 Additional educational modules and implementation tools for health workers: • WHO COVID-19 essential supplies forecasting tool (COVID-ESFT) assists governments, partners, and other stakeholders to forecast the necessary volume of personal protective equipment, diagnostic test equipment, consumable medical supplies, biomedical equipment for case management, and essential drugs for supportive care and treatment of COVID-19. • WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation provides algorithms and practical tools for clinicians working in acute care hospitals managing adult and paediatric patients with acute respiratory infection, including severe pneumonia, acute respiratory distress syndrome, sepsis and septic shock. This includes information on screening, testing, monitoring and treatments. • WHO Openwho.org clinical management course series hosts a full course series on COVID-19 which covers a holistic pathway of care for a patient, from screening and triage to rehabilitation, testing and treatments and palliative care. • Safety monitoring of molnupiravir for treatment of mild to moderate COVID-19 infection in low and middle-income countries using cohort event monitoring: a WHO study. 9. Uncertainties, emerging evidence and future research The guideline recommendations for COVID-19 therapeutics demonstrate remaining uncertainties concerning treatment effects for all outcomes of importance to patients. There is also a need for better evidence on prognosis and on values and preferences of patients with COVID-19. Here we outline key uncertainties for fluvoxamine and colchicine identified by the GDG, adding to those for remdesivir, nirmatrelvir- ritonavir, molnupiravir, JAK inhibitors, sotrovimab, convalescent plasma casirivimab-imdevimab, ivermectin, corticosteroids, remdesivir, hydroxychloroquine, lopinavir-ritonavir, and IL-6 receptor blockers identified when recommendations were initially formulated in previous versions of the living guideline. These uncertainties may inform future research, i.e. the production of higher certainty and more relevant evidence to inform policy and practice. We also outline emerging evidence in the rapidly changing landscape of trials for COVID-19. Ongoing uncertainties and opportunities for future research Fluvoxamine The panel's recommendation reflects the panel's perception that the current evidence does not justify using fluvoxamine to treat COVID-19. However, the panel has not implied that fluvoxamine was proven to be ineffective. Decisions to further investigate the effects of fluvoxamine for COVID-19 will likely hinge on how stakeholders perceive the opportunity cost of investigating the effects of fluvoxamine over other candidate therapies. The panel discussions illuminated the following knowledge gaps: • What are the effects of fluvoxamine in patients who suffer from a combination of non-severe COVID-19 at risk of deteriorating and significant symptoms of anxiety? • What are the side-effects of fluvoxamine therapy in patients with non-severe COVID-19 at risk of deteriorating? • What proportion of patients with non-severe COVID-19 at risk of deteriorating would be ineligible due to risk of pharmacological interactions? The panel surmised that, in the future, investigators would have to carefully consider whether fluvoxamine could still be compared with placebo or no treatment given that effective treatments are available. If the rationale to further investigate fluvoxamine is its advantageous cost and availability, non-inferiority designs may be considered. Colchicine The GDG panel believed that it was unlikely future studies would identify subgroups of patients who may benefit from colchicine. Remdesivir and nirmatrvelvir-ritonavir • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • resistance and efficacy against newer variants of interest; • efficacy in immunocompromised, vaccinated, children, pregnant patients, and other specific subgroups of patients • optimal duration of therapy • combination therapy with other COVID-19 drugs, and head-to-head comparison against other antiviral agents Molnupiravir • need for clinical data to investigate safety and applicability concerns (including in children, lactating or pregnant women, and men; and long-term impact on mutagenesis and cancer risk); • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • data to inform individual and population-level concerns, such as the emergence of resistance and efficacy against new variants; • comparative effectiveness of molnupiravir compared with other treatment options (eg. monoclonal antibodies or other antivirals) in the non-severe population, including combination therapy; • the relative intracellular nucleotide ratios of endogenous: molnupiravir cell lines and animal models to assess genetic toxicity; • how readily mutations arise under a selective pressure with NHC in vitro and molnupiravir in animal models and patients with SARS- CoV-2 infection; • if mutations arising under selective pressure in vitro, in vivo or in humans: ◦ confer a decreased antiviral activity for NHC; ◦ arise in the spike protein and/or do they confer an increase in replicative potential/transmission. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 125 of 142 JAK inhibitors • incremental benefit for patients receiving baricitinib and IL-6 receptor blockers together, rather than either drug individually; • relative benefits of tofacitinib and ruxolitinib to baricitinib; • safety and efficacy in children, and pregnant and lactating women. Sotrovimab • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19, in order to best identify patients who would most benefit from this intervention; • efficacy and safety for severe and critical seronegative COVID-19 patients, for patients infected with emerging variants, as well as in children and pregnant women. Convalescent plasma • effects in severe and critical illness (low to moderate certainty evidence for most patient-important outcomes); • long-term mortality and functional outcomes in COVID-19 survivors; • safety and efficacy in children, pregnant, and lactating women; • effects of high-titre convalescent plasma on mortality and other patient-important outcomes; • effects in patients with seronegative antibody status. Casirivimab-imdevimab • accurate clinical prediction guides to establish the individual patient risk of hospitalization in patients presenting with non-severe COVID-19 in order to best identify patients that would most benefit from this intervention; • dosing and administration routes in non-severe and severe/critical COVID-19 patients; • safety and efficacy in children and pregnant women. IL-6 receptor blockers • long-term mortality and functional outcomes in COVID-19 survivors; • safety data in terms of nosocomial infections; • data in children, pregnant patients and those that are already immunocompromised; • patients with non-severe COVID-19; • immunity and the risk of a subsequent infection, which may impact the risk of death after 28 days; • outcomes by different IL-6 receptor blocker dosing and optimal timing of drug initiation. Ivermectin Given the very low certainty in estimates for most critical outcomes of interest, the GDG felt that further high-quality clinical trials examining this drug would be essential before any recommendation for use as part of clinical care. This includes further RCTs examining both inpatients and outpatients and those with varying disease severities and using different ivermectin dosing regimens. The focus of these studies should be on outcomes important to patients such as mortality, quality of life, need for hospitalization, need for invasive mechanical ventilation and time to clinical or symptom improvement. Also, a better characterization of potential harms with ivermectin in patients with COVID-19 would be important. Hydroxychloroquine Although some uncertainty remains, the GDG panel felt that further research was unlikely to uncover a subgroup of patients that would benefit from hydroxychloroquine on the most important outcomes (mortality, mechanical ventilation) given the consistent results in trials across disease severity and location. Lopinavir-ritonavir Although some uncertainty remains, the GDG panel felt that further research was unlikely to uncover a subgroup of patients that would benefit from lopinavir-ritonavir on the most important outcomes (mortality, mechanical ventilation) given the consistent results in trials across disease severity and location. Corticosteroids • long-term mortality and functional outcomes in COVID-19 survivors; Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 126 of 142 • patients with non-severe COVID-19 (i.e. pneumonia without hypoxaemia); • outcomes, when used in combination with additional therapies for COVID-19, such as novel immunomodulators. It will become increasingly important to ascertain how these interact with systemic corticosteroids. All investigational therapies for severe and critical COVID-19 (including remdesivir) should be compared with systemic corticosteroids or evaluated in combination with systemic corticosteroids vs systemic corticosteroids alone; • immunity and the risk of a subsequent infection, which may impact the risk of death after 28 days; • outcomes, by different steroid preparation, dosing, and optimal timing of drug initiation. Emerging evidence The unprecedented volume of planned and ongoing studies for COVID-19 interventions – over 5000 RCTs as of May 2022 – implies that more reliable and relevant evidence will emerge to inform policy and practice (13) (see appendix). 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 registrations (13), the WHO website and other repositories, such as the COVID-NMA initiative. Whereas most of these studies are small and of variable methodological quality, a number of large, international platform trials (e.g. RECOVERY, SOLIDARITY, and DISCOVERY) are better equipped to provide robust evidence for a number of potential treatment options (14)(15)(16)(17). Such trials can also adapt their design, recruitment strategies, and selection of interventions based on new insights, exemplified by the uncertainties outlined above. Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 127 of 142 10. Authorship, contributions, acknowledgements Authorship, contributions, acknowledgements WHO would like to thank the collaborative efforts of all those involved to make this process rapid, efficient, trustworthy and transparent. WHO Therapeutics Steering Committee (updated for fluvoxamine and colchicine) The committee includes representatives from various WHO departments at headquarters and the regions and has been approved by the WHO Director of the Country Readiness Department, and the WHO Chief Scientist. The WHO Secretariat meets on a regular basis to discuss when to trigger guideline updates based on evidence updates from the WHO rapid review team, and other sources of evidence and selects the members of the Guideline Development Group (GDG) for the living guideline. Janet V Diaz (Lead, Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); John Appiah (Lead, Case Management, WHO Regional Office for Africa); Lisa Askie (Quality Assurance of Norms and Standards Department); Silvia Bertagnolio (Communicable and Noncommunicable Diseases Division/Clinical Team for COVID-19 Response); Chiori Kodama (WHO Regional Office for the Eastern Mediterranean); Krutika Kuppalli (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Marta Lado Castro-Rial (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Lorenzo Moja (Health Products Policy and Standards Department); Olufemi Oladapo (Sexual and Reproductive Health and Research Department); Dina Pfeifer (WHO Regional Office for Europe/Health Emergencies Programme); J Pryanka Relan (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva); Ludovic Reveiz (Evidence and Intelligence for Action in Health Department, Incident Management Systems for COVID-19, Pan American Health Organization); Vaseeharan Sathiyamoorthy (Research for Health, Science Division); Anthony Solomon (Neglected Tropical Diseases); Pushpa Wijesinghe (Lead, Case Management, Regional Office for South-East Asia). Supporting project officers: Julie Viry and Anne Colin (Clinical Team for COVID-19 Response, Health Emergencies Programme, Geneva). The WHO Therapeutics Steering Committee is fully responsible for decisions about guidance production and convening the GDG. Special thanks to the WHO Pharmacovigilance team for their support and contributions to this update: Noha Iessa and Shanti Pal. Guideline Development Group (GDG) for the update on fluvoxamine recommendation. For list of GDG members of previous recommendations, see here. Diptesh Aryal (Mediciti Hospital, Nepal); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); David Hui (Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong SAR, China); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Marc Mendelson (Division of Infectious Diseases & HIV Medicine at Groote Schuur Hospital, University of Cape Town, UTC); Giovanni Battista Migliori (Pulmonology, Istituti Clinici Scientifii Maygeri IRCCS); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Andre Ricardo Araujo Da Silva (Departamento de Materno Infantil, Universidade Federal Fluminense, Brazil); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for the update on colchicine recommendation. For list of GDG members of previous recommendations, see here. Diptesh Aryal (Mediciti Hospital, Nepal); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); David Hui (Stanley Ho Centre for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong SAR, China); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 128 of 142 Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Marc Mendelson (Division of Infectious Diseases & HIV Medicine at Groote Schuur Hospital, University of Cape Town, UTC); Giovanni Battista Migliori (Pulmonology, Istituti Clinici Scientifii Maygeri IRCCS); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Andre Ricardo Araujo Da Silva (Departamento de Materno Infantil, Universidade Federal Fluminense, Brazil); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for the update on remdesivir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Manai Hela (Emergency Medical Service Tunis, Tunisia); Frederique Jacquerioz Bausch (Department of Primary Care, University Hospital of Geneva, Switzerland); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for nirmatrelvir-ritonavir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Stephen Freedman (Department of Pediatrics, Cumming School of Medicine, University of Calgary, Canada); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Beverley Hunt (King's College London, United Kingdom); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Arthur Kwizera (Makerere University College of Health Sciences, Mulago National Referral Hospital ICU, Uganda); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Rakesh Lodha (Department of Paediatrics, All India Institute of Medical Sciences, India); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom). Guideline Development Group (GDG) for molnupiravir recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Patrick Gee (patient panel member, Virginia, United States); Matthias Gotte (University of Alberta, Canada); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Manai Hela (Emergency Medical Service Tunis, Tunisia); Beverley Hunt (King's College London, United Kingdom); Frederique Jacquerioz Bausch (Department of Primary Care, University Hospital of Geneva, Switzerland); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Fyezah Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 129 of 142 Jehan (Aga Khan University, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Arthur Kwizera (Makerere University College of Health Sciences, Mulago National Referral Hospital ICU, Uganda); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Imelda Mahaka (Pangaea Zimbabwe AIDS Trust, Harare, Zimbabwe); Emmanuel Nsutebu (Sheikh Shakhbout Medical City, Abu Dhabi); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Ronald Swanstrom (Department of Biochemistry & Biophysics of the University of North Carolina, United States); Tim Uyeki (Influenza Division, U.S. Centers for Disease Control and Prevention, United States); Sridhar Venkatapuram (King’s College London, United Kingdom); Ananda Wijewickrama (Ministry of Health, Sri Lanka). Guideline Development Group (GDG) for JAK inhibitors recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Carolyn S Calfee (University of California, San Francisco); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Beverley Hunt (King's College London, United Kingdom); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Sanjeev Krishna (St George’s University of London, United Kingdom); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College London, United Kingdom); Ananda Wijewickrama (Ministry of Health, Sri Lanka); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore). Guideline Development Group (GDG) for sotrovimab recommendation. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Fabian Alberto Jaimes Barragan (Antioquia University Medellin, Colombia); Duncan Chanda (Institute for Medical Research and Training, Zambia); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam); Ann De Sutter (Ghent Faculty of Medicine and Health Science, Belgium); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Beverley Hunt (King's College, London); Fyezah Jehan (Aga Khan University, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Yae Jean Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Sanjeev Krishna (St George’s University of London, United Kingdom); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Manu Shankar-Hari (King’s College London, United Kingdom), Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Ronald Swanstrom (University of North Carolina, United States); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College London, United Kingdom); Yee-Sin Leo (National Centre for Infectious Diseases, Singapore). Guideline Development Group (GDG) for convalescent plasma guideline. For list of GDG members of previous recommendations, see here. Wagdy Amin (Ministry of Health and Population, Egypt); Erlina Burhan (Infection Division Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia); Carolyn S Calfee (University of California, San Francisco); Maurizio Cecconi (Humanitas Research Hospital Milan, Italy); Vu Quoc Dat (Department of Infectious Diseases, Hanoi Medical University, Hanoi, Viet Nam); Heike Geduld (Emergency Medicine, Stellenbosch University, South Africa); Patrick Gee (patient panel member, United States of America); Nerina Harley (Royal Melbourne Hospital and Epworth Healthcare, Melbourne, Australia); Madiha Hashmi (Ziauddin University, Karachi, Pakistan); Sushil Kumar Kabra (All India Institute of Medical Sciences, New Delhi, India); Seema Kanda (patient panel member, Ontario, Canada); Leticia Kawano-Dourado (Research Institute, Hospital do Coração, São Paulo, Brazil); Niranjan Kissoon (Department of Paediatrics and Emergency Medicine, University of British Columbia, Vancouver, Canada); Greta Mino (Alcivar Hospital in Guayaquil, Ecuador); Natalia Pshenichnaya (Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russian Federation); Nida Qadir (Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States); Saniya Sabzwari (Aga Khan University, Karachi, Pakistan); Rohit Sarin (National Institute of Tuberculosis and Respiratory Diseases, New Delhi, India); Yinzhong Shen (Shanghai Public Health Clinical Center, Fudan University, Shanghai, China); Shalini Sri Ranganathan (University of Colombo, Sri Lanka); Miriam Stegemann (Charité - Universitätsmedizin Berlin, Germany); Sridhar Venkatapuram (King’s College, London); Ananda Wijewickrama (Ministry of Health, Sri Lanka). Therapeutics and COVID-19: living guideline - World Health Organization (WHO) 130 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) Methods chairs Gordon Guyatt (casirivimab-imdevimab, JAK inhibitors, nirmatrelvir-ritonavir), Bram Rochwerg (IL-6 receptor blockers, ivermectin, remdesivir and lopinavir-ritonavir, convalescent plasma, molnupiravir, remdesivir update), Reed Siemieniuk (hydroxychloroquine), Francois Lamontagne (corticosteroids, sotrovimab, colchicine, fluvoxamine, fluvoxamine, colchicine). Clinical chairs Michael Jacobs (casirivimab-imdevimab, IL-6 receptor blockers, ivermectin, remdesivir, hydroxychloroquine, lopinavir-ritonavir, JAK inhibitors, remdesivir update), Yee-Sin Leo (corticosteroids), Leticia Kawano-Dourado (convalescent plasma, sotrovimab, molnupiravir), Miriam Stegemann (fluvoxamine, colchicine). Methods resource persons Arnav Agarwal (University of Toronto, Canada); Thomas Agoritsas (University Hospitals of Geneva, Switzerland); Romina Brignardello- Petersen (McMaster University, Canada); Gordon H Guyatt (McMaster University, Canada); George Tomlinson (Department of Medicine, University Health Network, Toronto, Canada); Per Olav Vandvik (MAGIC, University of Oslo Norway); Linan Zeng (West China Second University Hospital, Sichuan University, Chengdu, China; McMaster University, Canada). Guideline Support Collaboration Committee which provides the coordination between WHO and MAGIC to allow the rapid development of the WHO guideline and its dissemination into the various publication platforms: Thomas Agoritsas (MAGIC, University Hospitals of Geneva); Janet Diaz (World Health Organization); Helen Macdonald (British Medical Journal); Gordon Guyatt (McMaster University, Canada); Per Olav Vandvik (MAGIC, University of Oslo); Julie Viry (World Health Organization). Temporary advisors: Special thanks to Professor Andrew Owen (Department of Molecular and Clinical Pharmacology, University of Liverpool) for his contributions in the pharmacokinetics of ivermectin, IL-6 receptor blockers, casirivimab-imdevimab, convalescent plasma and the monoclonal antibodies, JAK inhibitors, sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir update, fluvoxamine, colchicine). Special thanks to Professor Craig Thompson (University of Oxford) for his contributions in diagnostic testing as it relates to the casrivimab-imdevimab guideline. External reviewers Special thanks to the external reviewers for their insights on convalescent plasma, casrivimab-imdevimab, IL-6 receptor blockers, ivermectin, sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir, fluvoxamine and colchicine. Aula Abbara (Médecins Sans Frontières); Yaseen Arabi (King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia); Marcio da Fonseca (Médecins Sans Frontières); Richard Kojan (Alliance for International Medical Action); Carolina Nanclares (Médecins Sans Frontières); Saschveen Singh (Médecins Sans Frontières). Special thanks to Paula Dakin (Regeneron Pharmaceuticals Inc) who was invited to comment on on casirimab-imdevimab (version six) to identify factual errors, and to comment on clarity of language, contextual issues and implications for implementation. Their comments were considered taking into account the interests of Regeneron Pharmaceuticals Inc. Special thanks to Lisa Burry (Department of Pharmacy, Mont Sinai Hospital, Toronto) for her contributions to the Practical information sheets as clinical pharmacists (sotrovimab, molnupiravir, nirmatrelvir-ritonavir, remdesivir updates). Special thanks to Christine Tsang (Oxford University Hospitals NHS Foundation Trust, UK) for her contributions to the Practical information sheets as clinical pharmacists (molnupiravir, nirmatrelvir-ritonavir, remdesivir updates). Observer Sade Ogunsala (colchicine and fluvoxamine). Infographic Special thanks to the BMJ for providing the infographic for this guideline. Funding Many thanks to the Bill & Melinda Gates Foundation, Norwegian Directorate of Public Health and Germany. Special thanks to the MAGIC Evidence Ecosystem Foundation, which provides pro bono methodologic support. 131 of 142 Therapeutics and COVID-19: living guideline - World Health Organization (WHO) Meta-analysis teams Special thanks to the McMaster University LNMA team Arnav Agarwal (University of Toronto, Canada); Thomas Agoritsas (MAGIC; University Hospitals of Geneva, Switzerland); Jessica J Bartoszko (McMaster University, Canada); Romina Brignardello-Petersen (McMaster University, Canada); Derek K Chu (McMaster University, Canada); Rachel Couban (McMaster University, Canada); Andrea Darzi (McMaster University, Canada); Tahira Devji (McMaster University, Canada); Bo Fang (Chongqing Medical University, China); Carmen Fang (William Osler Health Network, Canada); Signe Agnes Flottorp (University of Oslo, Norway); Farid Foroutan (McMaster University, Canada); Long Ge (Lanzhou University, China); Gordon H Guyatt (McMaster University, Canada); Mi Ah Han (Chosun University, Republic of Korea); Diane Heels-Ansdell (McMaster University, Canada); Kimia Honarmand (Western University, Canada); Liangying Hou (Lanzhou University, China); Xiaorong Hou (Chongqing Medical University, China); Quazi Ibrahim (McMaster University, Canada); Ariel Izcovich (Servicio de Clinica Médica del Hospital Alemán, Argentina); Elena Kum (McMaster University, Canada); Francois Lamontagne (Université de Sherbrooke, Canada); Qin Liu (Chongqing Medical University, China); Mark Loeb (McMaster University, Canada); Maura Marcucci (McMaster University, Canada); Shelley L McLeod (Sinai Health, Canada); Sharhzad Motaghi, (McMaster University, Canada); Srinivas Murthy (University of British Columbia, Canada); Reem A Mustafa (McMaster University, Canada); John D Neary (McMaster University, Canada); Hector Pardo- Hernandez (Sant Pau Biomedical Research Institute, Spain); Anila Qasim (McMaster University, Canada); Gabriel Rada (Epistemonikos Foundation, Chile); Irbaz Bin Riaz (Mayo Clinic Rochester, United States of America); Bram Rochwerg (McMaster University, Canada); Behnam Sadeghirad (McMaster University, Canada); Nigar Sekercioglu (McMaster University, Canada); Lulu Sheng (Chongqing Medical University, China); Reed AC Siemieniuk (McMaster University, Canada); Ashwini Sreekanta (McMaster University, Canada); Charlotte Switzer (McMaster University, Canada); Britta Tendal (Monash University, Australia); Lehana Thabane (McMaster University, Canada); George Tomlinson (University of Toronto, Canada); Tari Turner (Monash University, Australia); Per Olav Vandvik (MAGIC; University of Oslo, Norway); Robin WM Vernooij (University Medical Center Utrecht, Netherlands); Andrés Viteri-García (Epistemonikos Foundation, Chile); Ying Wang (McMaster University, Canada); Liang Yao (McMaster University, Canada); Zhikang Ye (McMaster University, Canada); Dena Zeraatkar (McMaster University, Canada) (1)(2)(3). Special thanks to WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group for their publication: Association of administration of interleukin-6 antagonists with mortality and other outcomes among hospitalized patients with COVID-19: a prospective meta-analysis (116). Manu Shankar-Hari; Claire L Vale; Peter J Godolphin; David Fisher; Julian PT Higgins; Francesca Spiga; Jelena Savović; Jayne Tierney; Nor Arisah Misnan; Gabriel Baron; Julie S Benbenishty; Lindsay R Berry; Niklas Broman; Alexandre Biasi Cavalcanti; Roos Colman; Stefanie L De Buyser; Lennie PG Derde; Pere Domingo; Sharifah Faridah Syed Omar; Ana Fernandez-Cruz; Thijs Feuth; Felipe Garcia; Rosario Garcia-Vicuna; Isidoro Gonzalez-Alvaro; Anthony C Gordon; Richard Haynes; Olivier Hermine; Peter W Horby; Nora K Horick; Kuldeep Kumar: Bart N Lambrecht; Martin J Landray; Lorna Leal; David J Lederer; Elizabeth Lorenzi; Xavier Mariette; Nicolas Merchante; Nor Arisah Misnan; Shalini V Mohan; Michael C Nivens; Jarmo Oksi; Jose A Perez-Molina; Reuven Pizov; Raphael Porcher; Simone Postma; Reena Rajasuriar; Athimalaipet V Ramanan; Pankti D Reid; Abraham Rutgers; Aranzazu Sancho-Lopez; Todd B Seto; Sumathi Sivapalasingam; Arvinder Singh Soin; Natalie Staplin; John H Stone; Garth W Strohbehn; Jonas Sunden-Cullberg; Julian Torre- Cisneros; Larry W Tsai; Hubert van Hoogstraten; Tom van Meerten; Viviane Cordeiro Veiga; Peter Westerwheel; Srinivas Murthy; Janet V Diaz; John C Marshall; Jonathan A C Sterne. 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疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 疗法与2019冠状病毒病 动态指南 2022年7月14日 WHO/2019-nCoV/therapeutics/2022.4 © 世界卫生组织，2022年 保留部分版权。本作品可在知识共享署名——非商业性使用——相同方式共享3.0政府间组织（CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo/deed.zh） 许可协议下使用。 根据该许可协议条款，可为非商业目的复制、重新分发和改写本作品，但须按以下说明妥善引用。在对本作品进行 任何使用时，均不得暗示世卫组织认可任何特定组织、产品或服务。不允许使用世卫组织的标识。如果改写本作品，则 必须根据相同或同等的知识共享许可协议对改写后的作品发放许可。如果对本作品进行翻译，则应与建议的引用格式一 道添加下述免责声明：“本译文不由世界卫生组织（世卫组织）翻译，世卫组织不对此译文的内容或准确性负责。世卫 组织不对译文的内容或准确性负责。原始英文版本为应遵守的正本”。 对于任何与许可证相关的纠纷，将按照世界知识产权组织 (http://www.wipo.int/amc/en/mediation/rules/)的调解规则进 行调解。 建议的引用格式。疗法与2019冠状病毒病（COVID-19）：2022年7月14日日内瓦：世界卫生组织；2022 (WHO/2019- nCoV/therapeutics/2022.4)。许可协议：CC BY-NC-SA 3.0 IGO。 在版编目（CIP）数据。在版编目数据可查阅http://apps.who.int/iris。 销售、版权和许可。购买世卫组织出版物，参见http://apps.who.int/bookorders。提交商业使用请求和查询版权及许可 情况，参见 https://www.who.int/copyright。 第三方材料。如果希望重新使用本作品中属于第三方的材料，如表格、图形或图像等，应自行决定这种重新使用是 否需要获得许可，并相应从版权所有方获取这一许可。因侵犯本作品中任何属于第三方所有的内容而导致的索赔风险完 全由使用者承担。 一般免责声明。本出版物中使用的名称和材料的介绍并不代表世卫组织对任何国家、领土、城市或地区或其当局的 法律地位，或其边界或界线的划定表达任何意见。地图上的虚线表示可能尚未完全达成一致的大致边界线。 凡提及某些公司或某些制造商的产品时，并不意味着它们已为世卫组织所认可或推荐，或比其它未提及的同类公司 或产品更好。除差错和疏忽外，凡专利产品名称均冠以大写字母，以示区别。 世卫组织已采取一切合理的预防措施来核实本出版物中包含的信息。但是，已出版材料的分发无任何明确或含蓄的 保证。解释和使用材料的责任取决于读者。世卫组织对于因使用这些材料造成的损失概不负责。 联系人 世卫组织新型疾病临床评估和应对网络 EDCARN@who.int 世卫组织继续密切监测形势发展，以了解可能影响这一临时指导文件的任何变化。如果任何因素发生变化，世卫组 织将发布进一步的更新。如有任何因素发生改变，世卫组织将发布进一步更新。否则，本临时指导文件将在发布之日起 两年后失效。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 3 of 119 章节目录 1. 指南摘要 ................................................................................................................................................................................... 4 2. 缩略语 ....................................................................................................................................................................................... 6 3. 引言 ........................................................................................................................................................................................... 7 4. 本次更新的触发因素和下一步发展 ....................................................................................................................................... 8 5. 理解和应用世卫组织的疾病严重程度定义 ........................................................................................................................... 9 6. 疗法建议 ................................................................................................................................................................................. 10 6.1. 药物概述、建议及应用时要考虑的关键问题.............................................................................................................. 10 6.2. 氟伏沙明（2022年7月14日发布） ............................................................................................................................... 12 6.2.1. 作用机制 ............................................................................................................................................................... 16 6.3. 秋水仙碱（2022年7月14日发布） ............................................................................................................................... 17 6.3.1. 作用机制 ............................................................................................................................................................... 19 6.4. 奈玛特韦-利托那韦（2022年4月22日发布） .............................................................................................................. 20 6.4.1. 作用机制 ............................................................................................................................................................... 29 6.5. 瑞德西韦（2022年4月22日发布） ............................................................................................................................... 30 6.5.1. 作用机制 ............................................................................................................................................................... 35 6.6. 莫努匹拉韦（2022年3月3日发布） ............................................................................................................................. 36 6.6.1. 作用机制 ............................................................................................................................................................... 40 6.7. Janus激酶抑制剂（2022年1月14日发布） ................................................................................................................... 42 6.7.1. 作用机制 ............................................................................................................................................................... 50 6.8. 索托维单抗（2022年1月14日发布） ........................................................................................................................... 51 6.8.1. 作用机制 ............................................................................................................................................................... 55 6.9. 恢复期血浆（2021年12月7日发布） ........................................................................................................................... 57 6.9.1 作用机制 ................................................................................................................................................................ 63 6.10. 卡西瑞单抗-伊德维单抗（中和单克隆抗体）（2021年9月24日发布）.................................................................. 64 6.10.1 作用机制 .............................................................................................................................................................. 72 6.11. 白介素-6受体阻滞剂（2021年7月6日发布） ............................................................................................................. 73 6.11.1 作用机制 .............................................................................................................................................................. 78 6.12. 伊维菌素（2021年3月31日发布） .............................................................................................................................. 79 6.12.1作用机制 ............................................................................................................................................................... 83 6.13. 羟氯喹（2020年12月17日发布） ................................................................................................................................ 84 6.14. 洛匹那韦-利托那韦（2020年12月17日发布） ........................................................................................................... 88 6.15. 全身性皮质类固醇（2020年9月2日发布） ................................................................................................................ 92 7. 方法：本指南是如何编制的 ............................................................................................................................................... 100 8. 如何获取和使用本指南 ....................................................................................................................................................... 103 9. 不确定性、新出现的证据和未来研究 ............................................................................................................................... 105 10. 作者、贡献、致谢 ............................................................................................................................................................... 108 参考文献 ..................................................................................................................................................................................... 113 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 4 of 119 1. 指南摘要 临床问题：药物在治疗COVID-19患者中起什么作用？ 背景：随着大量随机对照试验近期完成和正在进行，COVID-19疗法的证据基础不断发展。本次更新增加了关于氟伏沙明和秋 水仙碱用于COVID-19非重症患者的新建议；前者参考了一项包含2196名患者的3项随机对照试验的系统综述，后者参考了13项随机 对照试验（18 172名患者）。 新建议：除非在临床试验环境中，指南制定小组(GDG)建议不要将氟伏沙明用于非重症患者。强烈建议不要将秋水仙碱用于非 重症患者。没有对重症或危重症患者提出建议，因为关于在该人群中使用两种药物的数据有限或不存在。 对于住院风险最高的COVID-19非重症患者，现在有几种治疗方案可供选择。在未进行试验中直接对比的情况下，使用了来自 动态网络荟萃分析（LNMA）的间接比较（见第7节“方法”），以便为药物之间的优劣比较及相关作用机制提供信息。选择将取 决于药物的可用性、给药途径（瑞德西韦仅静脉给药）、联合用药的药物、治疗持续时间以及试验中从出现症状到开始治疗的时 间。 新建议的理解：当根据证据做出建议时，GDG综合考虑了各种证据以评估相对利弊、价值观和偏好以及可行性问题。 当建议除临床试验外不对非重症患者使用氟伏沙明时，GDG认识到缺乏支持其疗效的明确作用机制，并且低至中等质量证据表 明其对住院、机械通气和死亡率几乎没有影响。该小组还注意到，在相关严重不良事件、已知显著药物相互作用，以及大比例停药 方面，在纳入的研究中缺乏可靠的数据。该小组预期，在使用氟伏沙明方面，患者的价值观和偏好不存在重要差异，因此建议除非 在临床试验的背景下，否则不使用该药物。 当建议不将秋水仙碱用于非重症患者时，GDG强调了证据（中等质量）表明其对住院、机械通气和死亡率几乎没有影响。GDG 还讨论了药物相互作用的已知风险，以及秋水仙碱狭窄的治疗窗口，特别是在有肝肾衰竭风险的患者中。秋水仙碱的毒性可能很严 重，有时是致命的。 先前的建议： 建议用于重度或危重症 COVID-19 患者： • 强烈建议使用全身性皮质类固醇； • 强烈建议使用白细胞介素-6（白介素-6）受体阻滞剂（托珠单抗或沙利鲁单抗）与皮质类固醇联合用药； • 强烈建议巴瑞替尼作为IL-6受体阻滞剂的替代品，与皮质类固醇联合使用； • 当可进行快速病毒基因分型并确认感染了易感的严重急性呼吸综合征冠状病毒2（ SARS-CoV-2 ）变异株时，有条件 建议对血清阴性患者使用卡西瑞单抗-伊德维单抗。 建议用于住院风险最高的非重症 COVID-19 患者： • 强烈建议使用奈玛特韦-利托那韦； • 有条件建议使用莫努匹拉韦； • 有条件建议使用索托维单抗； • 当可进行快速病毒基因分型并确认感染了易感的严重急性呼吸综合征冠状病毒2（ SARS-CoV-2 ）变异株时，有条件 建议使用卡西瑞单抗-伊德维单抗。 • 有条件建议使用瑞德西韦； 不建议用于非重症 COVID-19 患者： • 有条件建议不使用全身性皮质类固醇； • 强烈建议不使用恢复期血浆。 不建议用于住院风险低的非重症 COVID-19 患者： • 有条件建议不使用奈玛特韦-利托那韦； 不建议用于重症和危重症 COVID-19 患者： • 除非在临床试验中，否则建议不使用恢复期血浆； • 有条件建议不使用鲁索替尼和托法替尼。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 5 of 119 无论COVID-19疾病的严重程度如何，都建议不使用： • 强烈建议不使用羟氯喹； • 强烈建议不使用洛匹那韦-利托那韦； • 建议不在临床试验外使用恢复期血浆； 关于本指南：本版世界卫生组织（世卫组织）动态指南纳入了关于将氟伏沙明和秋水仙碱用于非重症COVID-19的新建议。当 世卫组织认为获得了足够的证据以对某个药物制定建议时，GDG通常会对该药进行评估。虽然GDG在制定建议时采取个体患者的视 角，但也会考虑对资源的影响、可接受性、可行性、公平和人权等因素。本指南根据可信赖指南的标准和方法制定。它得到动态网 络荟萃分析（LNMAs）(1)(2)(3)的支持。 更新和访问：这是本动态指南的第十一版（第十次更新）。它取代之前的版本（2020年9月2日、2020年11月20日、2020年12月 17日、2021年3月31日、2021年7月6日、2021年9月24日、2021年12月7日、2022年1月14日/2022年3月3日和2022年4月22日）。当前 的指南及其早期版本可通过世卫组织网站(4)、《英国医学杂志》(5)和MAGICapp（在线阅读，也可以PDF格式输出以供互联网接入 受限的读者使用）查阅。动态指南在线上平台(MAGICapp)中编写、传播和更新，使用用户友好的格式和易于浏览的结构，可容纳 动态更新的证据和建议，重点关注新内容的同时也在指南中更新原有建议。 世卫组织这份关于COVID-19治疗的动态指南与更长、更全面的COVID-19临床管理指南相关联(6)。关于使用药物预防（而非治 疗）COVID-19的指南已经单独发布在世卫组织网站(7)和《英国医学杂志》(8)上，得到动态网络荟萃分析（下称LNMA）的支持(9)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 6 of 119 2. 缩略语 ALT 丙氨酸转氨酶 ARDS 急性呼吸窘迫综合征 CAP 社区获得性肺炎 CI 置信区间 COVID-19 2019冠状病毒病 DOI 利益申报 eGFR 估算肾小球滤过率 FDA 美国食品和药物管理局 GDG 指南制定小组 GI 胃肠的 GRADE 建议分级的评估、制定和评价 GRC 准则审查委员会 IL-6 白细胞介素-6 IMV 有创机械通气 JAK Janus激酶 LNMA 动态网络荟萃分析 LMIC 低收入和中等收入国家 MAGIC 神奇证据生态系统基金会 MD 平均差 OIS 最优信息样本量 OR 优势比 PICO 对象、干预、对照、结局 PMA 前瞻性荟萃分析 RCT 随机对照试验 RR 相对危险度/风险比 SAE 严重不良事件 SSRI 选择性血清素再摄取抑制剂 TACO 输血相关循环超负荷 TRALI 输血相关性急性肺损伤 WHO 世界卫生组织 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 7 of 119 3. 引言 信息栏 截至 2022 年 5 月，已有超过 5.24 亿 COVID-19 确诊病例(10)。至此，大流行已经夺去了约 620 万人的生命(10)。疫苗接种 对一些高收入国家的病例数和住院人数正在产生实质性的影响，但全球疫苗获取仍然有限，这意味着许多人群依然脆弱 (10)(11)。即使在已接种疫苗的个体中，疫苗的保护期以及现有疫苗和 COVID-19的现有疗法对于新出现的 SARS-CoV-2变异株 的疗效尚不确定。 综上所述，仍然需要更有效的COVID-19治疗方法。COVID-19大流行——以及研究和错误信息的激增——凸显了对值得信 赖、容易获得和定期更新的动态指导文件的需求，以便正确理解新的研究结论，并为临床实践提供明确的建议(12)。 本动态指南根据 COVID-19现有和新的药物治疗的随机对照试验中新出现的证据制定。目前有 5000多项 COVID-19干预措 施的研究试验已经登记，并且正在进行或已经完成（见第 9节“新出现的证据”和链接的附录）(13)。其中包括在许多国家招募 大量患者的大型国家和国际平台试验（如 ACCT、“康复”试验、世卫组织“团结”试验、REMAP-CAP 和 ACTIV），它们采 用了务实和适应性的设计(14)(15)(16)(17)。正在进行的试验概况可以通过传染病数据观察站关于COVID-19临床试验登记的动态 系统综述(13)和世卫组织网站获得。 与本指南相关的几个动态网络荟萃分析纳入了新出现的试验数据，并允许对多种COVID-19治疗方法的有效性进行对比分 析。为了给动态指导文件提供信息，我们还使用了与COVID-19治疗相关的安全性、预后、患者价值观和偏好方面的其他相关 证据。最近更新的对住院治疗的COVID-19患者的232个风险预测模型的动态系统综述确定了两个有前途的风险预测工具，可为 本第十一版指南的建议提供信息；包括Jehi诊断模型和4C死亡率模型（详情参见6.1节）(18)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 8 of 119 4. 本次更新的触发因素和下一步发展 本世卫组织动态指南的第十一版涉及氟伏沙明和秋水仙碱用于COVID-19患者的情况。指南在LNMA关于COVID-19药物治疗 的更新分别纳入了三项和七项随机对照试验之后制定(1)。 图1显示了本世卫组织动态指南关注的其他正在研究的疗法，也发布在世卫组织门户网站上(4)。每一个点代表一周时间。在决 定指南要涵盖哪些疗法时，世卫组织考虑多种因素，包括可用证据在多大程度上可为建议提供参考等，并判断其他证据预期是否 以及何时可能会出现。世卫组织建立了一个常设指导委员会（见第10节）来评估新药建议的可能性并更新现有药物建议。 图 1. 评估中的 COVID-19 疗法 十二月十一月十月九月八月七月 氟伏沙明 索托维单抗 秋水仙碱 肝素 巴瑞替尼* 瑞德西韦* 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 9 of 119 5. 理解和应用世卫组织的疾病严重程度定义 信息栏 本指南适用于所有COVID-19患者。根据世卫组织的严重程度定义（见下文）(6)，基于COVID-19病情的严重程度可能给出 不同的建议。上述定义避免了必须就医才能确定患者所属亚组的情况。 世卫组织 COVID-19 疾病严重程度定义 • COVID-19 危重症——定义为符合急性呼吸窘迫综合征（ARDS）、败血症、败血性休克的标准或其他通常需要提供 维持生命治疗（如有创或无创机械通气或升压药治疗）的疾病的标准。 • COVID-19 重症——定义为符合以下任何一项： • 室内空气条件下血氧饱和度<90%； • 肺炎体征 • 严重呼吸窘迫体征（成人使用辅助肌、不能说完整的句子，呼吸频率>30 次/分钟；儿童非常严重的胸部凹陷、 发出咕噜声、中央性紫绀或出现肺炎体征以及任何其他一般危险体征，包括无法哺乳或饮水、嗜睡、抽搐或意 识水平降低）。 • 非重症 COVID-19——定义为不符合任何 COVID-19重症或危重症标准。 警告：GDG指出，用血氧饱和度90%作为阈值来界定COVID-19重症是人为设定的，在定义患者病情的严重程度时应谨慎 解读。例如，临床医生必须自己判断低血氧饱和度对于患有慢性肺病的患者而言是重症的体征还是正常体征。同样，对于肺部 正常的患者，在室内空气条件下血氧饱和度为90-94%可能被临床医生解读为不正常，并且对于临床表现每况愈下的患者，则可 能解读为重症的早期体征。一般来说，如情况存疑，GDG建议宁可将病情归于重症。 信息图说明了三个疾病严重程度组别和在实践中应用的关键特征。 信息图由《英国医学杂志》和神奇证据生态系统基金会共同制作；由Will Stahl-Timmins设计（见《英国医学杂志》快速建 议）。 人口 疾病严重程度 重症 危重症 需要维持生命治疗无重症或 危重症体征 本建议仅适用于有如下特征的人群： 确诊 COVID-19的 患者 室内空气条件下 血氧饱和度<90% 非重症 严重呼吸窘迫体征 肺炎体征 急性呼吸窘迫 综合征 败血症 败血性休克 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 10 of 119 6. 疗法建议 决策考虑因素 6.1. 药物概述、建议及应用时要考虑的关键问题 信息栏 更新 信息图总结了世卫组织的建议，并根据世卫组织的严重程度标准进行了映射。在应用这些建议时，临床医生还应考虑以下关键 问题： 如何在治疗方法之间进行选择 对于COVID-19非重症患者以及COVID-19重症或危重症患者，有几种治疗方案可供选择。选择将取决于药物的可用性、给药途 径（瑞德西韦和单克隆抗体仅静脉给药）、联合用药的药物、治疗持续时间以及试验中从出现症状到开始治疗的时间。有些药物可 以联合使用（即对重症或危重COVID-19），而另一些则可用作替代药物。推荐的治疗组合基于来自证明了额外益处的试验中直接 比较，例如对于COVID-19重症或危重症患者，在全身性皮质类固醇的基础上增加巴瑞替尼或白细胞介素-6受体阻滞剂。 在未在试验中对各种治疗进行直接对比的情况下，使用了来自LNMA的间接比较（见第7节“方法”），以便为药物之间的优 劣比较和相关作用机制提供信息。为了展示替代疗法的利弊，我们提供了一个交互式决策支持工具，该工具也可用于共享决策。 对特定SARS-CoV-2变异株的疗效可能有所差异。例如，先前建议的抗体可能对Omicron BA.1/BA.2 变异株的效果较差。 如何确定住院风险最高的非重症COVID-19患者 一些药物建议仅适用于住院风险最高的人，因为如果每个COVID-19非重症患者都接受该治疗，其益处（绝对意义上的）将是 微不足道的；相反，一些治疗应保留给住院风险最高的患者，并在病程早期给予。小组为COVID-19确定了10%的住院风险阈值，在 此阈值以上的大多数非重症患者会希望接受治疗（参见第7节）。 随着病毒和疫苗接种模式的演变，全球背景不断变化，因而难以可靠地识别风险最高的人群，这就使针对当地情况进行模型验 证变得更加重要。在奥密克戎传播之前，对COVID-19的232个风险预测模型进行的动态系统综述确定了两个有前途的风险预测工具 (18)。这些工具一致认为，最高风险人群的典型特征包括年龄较大、免疫抑制和/或慢性病患者，未接种疫苗作为需考虑的额外风险 因素。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 11 of 119 新增人群 重症 危重 需要生命维持治疗 疾病严重程度 COVID19 确诊患者 室内空气条件下 <90% 干预措施 强烈建议使用 弱或有条件建议 使用 弱或有条件建议 强烈建议不使用 羟氯喹 洛匹那韦-利托那韦 恢复期 血浆 奈玛特韦和 利托那韦 皮质类固醇 白介素-6受体阻滞剂 取决于可用性 以及临床和环 境因素 莫努匹拉韦 应仅在临床试验中予以考虑 应仅在临床试验中予以考虑 应仅在巴瑞替尼和白介素-6受体阻滞剂 都不可用时予以考虑 鲁索替尼和托法替尼 伊维菌素 索托维单抗 瑞德西韦 卡西瑞单抗和 伊德维单抗 卡西瑞单抗和 伊德维单抗 对奥密克戎BA1 变异株疗效 有限的证据 用于住院风险最 高的患者 使用交互式多重比较工具 来比较和选择治疗方法 i i i i i i ! 非重症 重症 症体征 本建议仅适用于具有 以下特征的人： 严重呼吸 窘迫体征 肺炎体征 脓毒症 脓毒性休克 急性呼吸窘迫 综合征 应实施缓解策略以减 少潜在危害 白介素-6受体阻滞剂 或 巴瑞替尼 匹配 用于SARSCoV抗体血清 阴性患者 皮质类固醇 恢复期 血浆 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 12 of 119 6.2. 氟伏沙明（2022年7月14日发布） 用于非重症COVID-19患者 实用信息 GDG建议不在临床试验环境之外使用氟伏沙明治疗COVID-19患者，因此实用考虑因素与此药的相关性不大。 决策证据 利弊 在COVID-19非重症患者中，氟伏沙明很可能对死亡率几乎没有影响，可能对机械通气和住院治疗几乎没有影响，没有报告关 于症状消除和不良反应导致停药的数据。GDG的结论是，利益与潜在危害的权衡不支持治疗。 按年龄和症状出现时间对比氟伏沙明和标准治疗的计划亚组分析不支持任何相对效果差异，而由于试验仅招募了COVID-19非 重症患者无法按疾病严重程度进行对比分析。 证据的确定性 证据摘要参考了纳入LNMA的3项试验，有2225名参与者。最大一项试验（n = 1480）仅从巴西招募患者(19)。 证据质量评定为：死亡率为中等质量（由于严重的间接性），机械通气为低质量（由于严重的间接性、不精确性，以及对偏 倚风险的一些担忧），以及住院为低质量（由于严重的不精确性和偏倚风险）。小组成员承认其对证据确定性的评估可能与其他 已发表的荟萃分析不同(20)，并指出为明显益处而提前停止试验可能使最大试验的结果发生偏倚。他们认为，尽管停止试验的规则 是预先确定的，但该决定基于对一项重要性存疑的综合结果的影响估计，同时重要事件的数量较低。对这项仅在单一国家进行的 试验，小组还对其不确定的适用性表示关切。 价值观和偏好 鉴于商定的价值观和偏好声明（见第7节），GDG推断，基于现有证据，几乎所有充分知情的患者都会选择不接受氟伏沙明治 疗COVID-19。GDG认为，可行性、可接受性、公平性和成本等其他考虑因素不会影响这一具体建议。具体而言，在本COVID-19 药物指南中，GDG没有考虑氟伏沙明作为抗抑郁药的潜在作用。 资源和其他考虑因素 该小组承认，非重症COVID-19的有效治疗替代品价格昂贵，这可能会限制其在资源受限地区的可用性。然而，尽管与用于治 疗COVID-19的其他药物相比，氟伏沙明相对便宜并且广泛可用（包括在低收入环境中），但证据无法证明在任何地方使用氟伏沙 明治疗非重症COVID-19的合理性。尽管氟伏沙明的成本可能很低，但GDG小组担忧其将注意力和资源从更有可能提供益处的干预 措施上引开的风险。为避免所制定的建议可能永久化和合法化更有效药物可及性的不均等，小组认为最好强调需要更加公平的获 得有效治疗方案的机会。 理由 当基于证据建议除临床试验外不对COVID-19非重症患者使用氟伏沙明时，GDG强调了缺乏明确的作用机制，且低确定性证据 显示其对住院和机械通气几乎没有影响，中等质量证据显示其对死亡率几乎没有影响，同时缺乏关于因已知的显著药物相互作用 而引起的可归因于该药物的严重不良反应方面的可靠数据。该小组指出，在最大的一项试验中，对比安慰剂组，氟伏沙明组的更 多患者停用了该研究性产品。GDG注意到针对非重症COVID-19存在有效的治疗替代方案，因此预期患者的价值观和偏好不存在重 要差异。小组认为资源考虑、可及性、可行性和公平性（这些因素的摘要见“决策证据”部分）等其他考虑因素不会影响这一特 定建议。 仅限研究环境 新增 我们建议不使用氟伏沙明，除非在临床试验的背景下（建议仅在研究环境中使用）。 • 对于COVID-19非重症患者建议使用几种治疗方案，包括奈玛特韦-利托那韦、莫努匹拉韦和瑞德西韦。 • 要在治疗方案之间进行选择，参阅第6.1节和决策支持工具，其中显示了这些选项的利弊。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 13 of 119 适用性 特定人群：所纳入的随机对照试验都没有招募儿童，因此本建议对儿童的适用性目前尚不确定。然而，小组认为没有理由假 定患有COVID-19的儿童对氟伏沙明的治疗会有不同的反应。 临床问题/PICO 对象：COVID-19非重症患者 干预：氟伏沙明 对照：不使用氟伏沙明 摘要 关于氟伏沙明的LNMA参考了三项随机对照试验，共招募了2225名门诊非重症患者。所有随机对照试验均已登记，其中两项试 验在一份同行评议的期刊上发表。三项研究均在门诊进行。纳入的研究均未招募儿童。此表显示了随机对照试验的特征。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，氟伏沙明与 标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息(1)。 根据TOGETHER试验(19)的数据，按年龄（儿童、成人、老年人）和症状出现时间（0-3天、4-7天）没有观察到对主要结局的 可信亚组效应。由于缺乏可用数据，无法根据疾病严重程度、年龄和慢性病（绝对效果），血清学状态和疫苗接种状态划分进行计 划的亚组分析。 结局 时间表 研究结果和衡量标准 对照 不使用氟伏沙明 干预 氟伏沙明 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.68 （95%置信区间 0.33 -1.32） 基于2项研究1649名 参与者的数据。 （随机对照） 4 每1000人 3 每1000人 中等 由于严重的 间接性 1 死亡率很可能几乎 没有差异 差异：每1000人减少1例 （95%置信区间减少3例—增加1例） 机械通气 优势比0.73 （95%置信区间 0.38- 1.4） 基于2项研究1649名 参与者的数据。 （随机对照） 18 每1000人 13 每1000人 低 由于严重的间接性 和不精确性2 机械通气方面可能 几乎没有差异 差异：每1000人减少5例 （95%置信区间 减少 11例—增加7例） 住院 高风险 优势比0.7 （95%置信区间 0.34- 1.23） 基于3项研究2196名 参与者的数据。 （随机对照） 35 每1000人 25 每1000人 低 由于非常严重的 不精确性3 氟伏沙明可能减少 住院治疗 差异：每1000人减少10例 （95%置信区间减少23例—增加8例） 住院 较高风险 优势比0.7 （95%置信区间 0.34- 1.23） 基于3项研究2196名 参与者的数据。 （随机对照） 60 每1000人 43 每1000人 低 由于非常严重的 不精确性4 氟伏沙明可能减少 住院治疗 差异：每1000人减少17例 （95%置信区间减少39例—增加13例） 住院 最高风险 优势比0.7 （95%置信区间 0.34- 1.23） 基于3项研究2196名 参与者的数据。 （随机对照） 100 每1000人 72 每1000人 低 由于非常严重的 不精确性5 氟伏沙明可能减少 住院治疗 差异：每1000人减少28例 （95%置信区间减少64例—增加20例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 14 of 119 结局 时间表 研究结果和衡量标准 对照 不使用氟伏沙明 干预 氟伏沙明 证据的确定性 （证据质量） 纯文本摘要 导致停药的 不良反应 尚无数据 氟伏沙明的效果 尚不清楚 症状消除时间 尚无数据 氟伏沙明的效果 尚不清楚 1. 间接性：严重。整个人群的基线风险非常低，意味着对死亡率的任何影响都将很小。有些人的基线风险要高得多，但不 易识别。对于这些患者，氟伏沙明有可能对死亡率有重要影响。 2. 间接性：严重。一些患者的机械通气风险可能要高得多。不精确性：严重。 3. 不精确性：非常严重。可信区间包括重要的利弊。 4. 不精确性：非常严重。可信区间包括重要的利弊。 5. 不精确性：非常严重。可信区间包括重要的利弊。 临床问题/PICO 对象：COVID-19 非重症患者 干预：氟伏沙明 对照：奈玛特韦-利托那韦 结局 时间表 研究结果和衡量标准 对照 奈玛特韦-利托那韦 干预 氟伏沙明 证据的确定性 （证据质量） 纯文本摘要 死亡率 0 每1000人 3 每1000人 非常低 由于严重的间接性、 不精确性和严重的 偏倚风险1 对死亡率的影响 非常不确定 差异：每1000人增加3例 （95%置信区间增加1例——增加5例） 机械通气 尚无数据 2 对机械通气的 作用未知 住院 优势比4.54 （95%置信区间 1.32- 12.78） （随机对照） 5 每1000人 22 每1000人 低 由于严重的不精确 性和偏倚风险3 奈玛特韦-利托那韦 比氟伏沙明更能 减少住院治疗 差异：每1000人增加17例 （95%置信区间增加2例 — 增加55例） 导致停药的不良反应 尚无数据 对不良反应的影响 尚不清楚 症状消除时间 尚无数据 对症状消除时间的 影响尚不清楚 1. 偏倚风险：严重。EPIC-HR研究被提前停止以求益处。间接性：严重。整个人群的基线风险非常低，意味着对死亡率的 任何影响都将很小。有些人的基线风险要高得多，但不易识别。对于这些患者，氟伏沙明有可能对死亡率有重要影响。 不精确性：严重。事件非常少。 2. 间接性：严重。一些患者的机械通气风险可能要高得多。不精确性：严重。 3. 偏倚风险：严重。奈玛特韦-利托那韦的研究（EPIC-HR）被提前停止以求益处。不精确性：严重。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 15 of 119 临床问题/PICO 对象：COVID-19非重症患者 干预：氟伏沙明 对照：莫努匹拉韦 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 氟伏沙明 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比5.74 （95%置信区间 0.95 -56.11） （随机对照） 0.4 每1000人 2 每1000人 低 由于严重的间接性 和不精确性11 死亡率可能几乎 没有差异 差异：每1000人增加1.6例 （95%置信区间 减少0.02例—增加21.56例） 机械通气 优势比1.77 （95%置信区间 0.19- 10.6） （随机对照） 8 每1000人 14 每1000人 非常低 由于严重的 间接性和 非常严重的 不精确性 2 对机械通气的影响 不确定 差异：每1000人增加6例 （95%置信区间减少 6例 — 增加71例） 住院 优势比1.31 （95%置信区间 0.52 -2.98） （随机对照） 19 每1000人 25 每1000人 低 由于非常严重的 不精确性3 住院治疗方面可能 几乎没有差异 差异：每1000人增加6例 （95%置信区间减少 9例 — 增加36例） 导致停药的 不良反应 尚无数据 对不良反应的影响 尚不清楚 症状消除时间 尚无数据 对症状消除时间的 影响尚不清楚 1. 间接性：严重。整个人群的基线风险非常低，意味着对死亡率的任何影响都将很小。有些人的基线风险要高得多，但不 易识别。对于这些患者，氟伏沙明有可能对死亡率有重要影响。不精确性：严重。事件非常少。 2. 间接性：严重。一些患者的机械通气风险可能要高得多。不精确性：非常严重。 3. 不精确性：非常严重。可信区间包括重要的利弊。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 16 of 119 临床问题/PICO 对象：非重症COVID-19 患者 干预：氟伏沙明 对照：瑞德西韦 结局 时间表 研究结果和衡量标准 对照 瑞德西韦 干预 氟伏沙明 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.87 （95%置信区间 0.27 - 2.85） （随机对照） 3 每1000人 3 每1000人 低 由于严重的间接性 和不精确性1 死亡率可能几乎 没有差异 差异：每1000人减少0例 （95%置信区间减少2例—增加6例） 机械通气 优势比1.63 （95%置信区间 0.19 - 11.23） （随机对照） 8 每1000人 13 每1000人 非常低 由于严重的间接性 和非常严重的 不精确性 2 对机械通气的影响 不确定 差异：每1000人增加5例 （95%置信区间减少6例—增加75例） 住院 优势比2.76 （95%置信区间 0.62 - 12.07） （随机对照） 9 每1000人 24 每1000人 低 由于非常严重的 不精确性3 瑞德西韦可能 比氟伏沙明更能 减少住院治疗 差异：每1000人增加15例 （95%置信区间减少3例—增加90例） 导致停药的 不良反应 尚无数据 对不良反应的影响 尚不清楚 症状消除时间 尚无数据 对症状消除时间的 影响尚不清楚 • 间接性：严重。整个人群的基线风险非常低，意味着对死亡率的任何影响都将很小。有些人的基线风险要高得多，但不 易识别。对于这些患者，氟伏沙明有可能对死亡率有重要影响。不精确性：严重。事件非常少。 • 间接性：严重。一些患者的机械通气风险可能要高得多。不精确性：非常严重。 • 不精确性：非常严重。 6.2.1. 作用机制 氟伏沙明是一种选择性血清素再摄取抑制剂（SSRI），被批准为抗抑郁药。氟伏沙明的抗抑郁作用与抑制大脑中血清素转运 体有关，其作用是增加突触间隙中血清素的浓度。在COVID-19方面，已经提出了几种推定的抗炎或抗病毒作用机制(21)(22)。首 先，由于血小板和/或肺部的血清素转运体抑制，可以假定抗炎特性，但这是基于非COVID-19疾病模型的间接证据。其次，已经 提出了通过sigma-1受体的激动作用产生的宿主导向的抗病毒特性，对于这一点，存在来自其他病毒参与RNA复制的一些证据，但 目前还没有已发表的临床前研究可以直接证明或反驳其对于COVID-19的机制。因此，合理性要求对于抗炎或抗病毒机制的间接证 据予以解释，这些机制目前尚未得到临床前证实，并且与抑郁症的机制和作用部位没有直接关系。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 17 of 119 6.3. 秋水仙碱（2022年7月14日发布） 用于非重症COVID-19患者 实用信息 GDG强烈建议不使用秋水仙碱治疗COVID-19非重症患者，因此实用考虑因素的相关性不大。 决策证据 利弊 在非重症 COVID-19 患者中，秋水仙碱很可能对死亡率和机械通气几乎没有影响，对住院治疗几乎没有影响，并且可能增加 导致停药的不良反应的概率。小组讨论了药物相互作用的风险，以及秋水仙碱狭窄的治疗窗口，特别是在有肝肾衰竭风险的患者 中。秋水仙碱的毒性可能很严重，有时是致命的。秋水仙碱对比标准治疗的计划亚组分析没有显示在疾病严重程度和年龄（儿 童，成人，老年人）方面有不同的相对效应，未有从发病开始的数据报告。 证据的确定性 秋水仙碱的证据摘要参考了一项系统综述，包括13项试验，涉及18172名参与者。死亡率方面的证据最为丰富，其他结局的报 告不完整（例如，关于不良反应的五项试验，有598名参与者）。一项包含4488名参与者的单项试验(23)几乎提供了所有有关住院 治疗的证据，但被过早停止。 证据确定性的评级如下：死亡率和机械通气方面为中等（因间接性调低评级）；住院治疗方面为低（因不精确和偏倚风险而 调低）；导致停药的不良反应，低（因不精确性和偏倚风险而调低）。 价值观和偏好 鉴于商定的价值观和偏好声明（见第7节），GDG推断，基于现有关于相对利弊的证据，几乎所有充分知情的患者都会选择不 接受秋水仙碱。GDG认为，可行性、可接受性、公平性和成本等其他考虑因素不影响这一具体建议。 资源和其他考虑因素 该小组承认，针对非重症COVID-19的有效治疗替代品价格昂贵，这可能会限制其在资源受限地区的可用性。然而，尽管与用 于COVID-19的其他药物相比，秋水仙碱相对便宜并且广泛可用（包括在低收入环境中），但证据无法证明在任何地方使用秋水仙 碱治疗非重症COVID-19的合理性。尽管秋水仙碱的成本可能很低，但GDG担忧其将注意力和资源从更有可能提供益处的干预措施 上引开的风险。为避免所制定的建议可能永久化和合法化更有效药物可及性的不均等，小组认为最好强调需要更加公平的获得有 效治疗方案的机会。 理由 当基于证据强烈建议不对COVID-19非重症患者使用秋水仙碱时，GDG强调了其对死亡率和机械通气没有影响的中等质量证 据，以及其对住院治疗没有影响的低质量证据，但治疗可能引起危害。具体而言，该小组认识到腹泻、血细胞减少和其他毒性的 风险（特别是在患有肾衰竭或有此风险的患者中）对COVID-19非重症患者可能很重要。GDG注意到COVID-19非重症存在有效治 疗替代方案，因此预期患者的价值观和偏好不存在重要差异。小组不认为其他考虑因素，如资源考虑、可及性、可行性和公平性 （这些因素的摘要见“决策证据”部分）不会影响这一特定建议。 适用性 特定人群：所纳入的随机对照试验均未招募儿童，因此本建议对儿童的适用性目前尚不确定。然而，小组不认为有理由假定 强烈建议不使用 新增 我们建议不使用秋水仙碱进行治疗（强烈建议不使用）。 • 对于COVID-19非重症患者，建议使用几种治疗方案，包括奈玛特韦-利托那韦、莫努匹拉韦和瑞德西韦。 • 要在治疗方案之间进行选择，参阅第6.1节和决策支持工具，其中显示了这些选项的利弊。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 18 of 119 患有COVID-19的儿童对秋水仙碱的治疗会有不同的反应。 临床问题/PICO 对象：非重症COVID-19患者 干预：秋水仙碱 对照：标准治疗 摘要 秋水仙碱的系统综述纳入了13项试验，招募了18 172名患者。所有试验均已登记。这些研究均未招募儿童。此表显示了随机对 照试验的特征。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，秋水仙碱与 标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息(1)。 根据COLCORONA试验(23)的数据，按年龄（儿童、成人、老年人）和疾病严重程度（非重症、重症）没有观察到对主要结局 的可信亚组效应。由于缺乏可用数据，无法根据症状出现时间、年龄和慢性病（绝对效果），血清学状况和疫苗接种状况划分进行 计划的亚组分析。 结局 时间表 研究结果和衡量标准 对照 标准治疗 干预 秋水仙碱 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.84 （95%置信区间 0.5 - 1.17） 基于来自10项研究的 17914名参与者的 数据。 （随机对照） 4 每1000人 3 每1000人 中等 由于严重的 间接性1 秋水仙碱很可能 对死亡率几乎 没有影响 差异：每1000人减少1例 （95%置信区间 减少2例 — 增加1例） 机械通气 优势比0.75 （95%置信区间 0.37 - 1.26） 基于5项研究中 12 746名参与者的 数据。 （随机对照） 9 每1000人 7 每1000人 中等 由于严重的 间接性2 秋水仙碱很可能 对机械通气几乎 没有影响 差异：每1000人减少2例 （95%置信区间减少6例 — 增加2例） 住院 试验中的风险 优势比0.68 （95%置信区间 0.27 - 1.57） 基于3项研究4949名 参与者的数据。 （随机对照） 35 每1000人 24 每1000人 中等 由于严重的 不精确性3 秋水仙碱很可能 对住院几乎没有 影响 差异：每1000人减少1例 （95%置信区间减少25例 — 增加19例） 住院 较高风险 优势比0.68 （95%置信区间 0.27 - 1.57） 基于3项研究4949 名参与者的数据。 （随机对照） 60 每1000人 42 每1000人 中等 由于严重的 不精确性4 秋水仙碱很可能 对住院几乎没有 影响 差异：每1000人减少18例 （95%置信区间减少43例 — 增加31例) 住院 最高风险 优势比0.68 （95%置信区间 0.27 - 1.57） 基于3项研究4949 名参与者的数据。 100 每1000人 70 每1000人 低 由于非常严重的 不精确性5 秋水仙碱可能 对住院几乎没有 影响 差异：每1000人减少30例 （95%置信区间减少71例 — 增加49例) 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 19 of 119 结局 时间表 研究结果和衡量标准 对照 标准治疗 干预 秋水仙碱 证据的确定性 （证据质量） 纯文本摘要 （随机对照） 导致停药的 不良反应 基于5项研究中 598名参与者的 数据。 （随机对照） 0 每1000人 34 每1000人 低 由于严重的 偏倚风险和严重的 不精确性6 秋水仙碱可能会 增加导致停药的 严重不良反应的 风险。 差异：每1000人增加34例 1. 间接性：严重。 2. 间接性：严重。不精确性：不严重。可信区间包括微小益处。 3. 不精确性：严重。可信区间上限包括对住院治疗的微小且不重要的影响（每1000人减少4例）。 4. 不精确性：严重。可信区间上限包括对住院治疗的微小且不重要的影响（每1000人减少4例）。 5. 不精确性：非常严重。 6. 偏倚风险：严重。不精确性：严重。 6.3.1. 作用机制 秋水仙碱是一种抗炎药，用于治疗痛风、复发性心包炎、家族性地中海热和其他炎症适应症。理论上，有几种可能的作用机 制可以消除COVID-19中发现的炎症相关病理学(24)(25)，其中包括降低中性粒细胞趋化性，抑制炎症体信号传导以及减少白细胞 介素-1b（白介素-1b）等细胞因子的产生。指南发布时，尚无已发表的来自SARS-CoV-2感染的动物模型数据支持或反驳秋水仙碱 在相关疾病病理学中的临床前疗效或危害。据推测，其作用机制与秋水仙碱已被批准的适应症相似，但其对COVID-19作用的合理 性要求接受COVID-19与其他疾病之间存在相似性的假设。在调查的剂量和时间表方面，针对COVID-19所做的试验之间存在显著 差异。在网络荟萃分析纳入的研究中，剂量范围在每日0.5至2毫克之间，疗程在6至30天之间，一些研究每日给药一次，另一些每 日给药两次，还有一些每日给药三次。此外，一些研究使用的给药时间表在疗程中发生改变，以一种剂量或时间表开始，而后在 预设的间隔后更改为另一种不同的剂量或时间表。秋水仙碱的药代动力学在0.5mg至1.5mg剂量之间呈剂量线性(26)(27)，但网络荟 萃分析中包含的研究之间的实质性差异使得无法对与剂量和时间表相关的结局差异给出有力解释。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 20 of 119 6.4. 奈玛特韦-利托那韦（2022年4月22日发布） 信息栏 关于奈玛特韦-利托那韦用于COVID-19非重症患者的建议已于2022年4月22日作为世卫组织动态指南的第十版发布，并在《英国 医学杂志》上作为快速建议发布。指南在关于药物疗法的LNMA提供了两项随机对照试验之后制定(1)。在本第十一版指南中，没有 对奈玛特韦/利托那韦的建议进行修订。 用于住院风险最高的非重症COVID-19患者 实用信息 途径、剂量和持续时间：三个实用问题摘要提供了其他考虑因素（奈玛特韦-利托那韦用于COVID-19，奈玛特韦-利托那韦用 于治疗COVID-19的给药，接受奈玛特韦-利托那韦治疗COVID-19的患者的安全性和监测）。以下是关键要点的简明摘要： • 根据在本建议参考的大型试验中所评估的方案，奈玛特韦-利托那韦的推荐剂量为300mg（两片150mg片剂）奈玛特韦和 100mg利托那韦，每日12小时一次，连续5天。 • 在肾功能不全（肾小球滤过率 30-59 mL/min）的情况下，剂量减少为150mg奈玛特韦和100mg利托那韦，每日12小时一 次，连续5天。 • 应在病程中尽早给药。在纳入的研究中，奈玛特韦-利托那韦在发病后5天内给药。 • GDG的结论是，不应向患有COVID-19的儿童、哺乳期妇女或孕妇提供奈玛特韦-利托那韦。 在考虑对任何患者使用奈玛特韦-利托那韦时，临床医生需要认真考虑药物相互作用。在此方面，利物浦COVID-19药物相互 作用检查工具可能有用(28)。 决策证据 利弊 在风险最高的患者中，奈玛特韦-利托那韦很可能明显减少住院治疗，其益处显然大于危害，据此强烈建议使用该药物。 在COVID-19非重症患者中，奈玛特韦-利托那韦可能会减少住院治疗（中等确定性证据）。该药可能对死亡率几乎没有影响 （低确定性证据）。关于症状消除或机械通气时间，没有报告数据。使用奈玛特韦-利托那韦治疗不会增加导致停药的不良反应的 概率（高确定性证据），尽管与安慰剂相比，使用奈玛特韦-利托那韦治疗发生腹泻和味觉障碍（味觉丧失）的频率更高。 GDG承认，缺乏与耐药性出现相关的信息，需要更多的数据来为本建议提供信息。 证据的确定性 关于奈玛特韦 -利托那韦的证据摘要参考了LNMA研究纳入的两项试验（EPIC-SR和EPIC-HR），共有3100名参与者 (1)(29)(30)。 证据的确定性被评为：减少住院方面：中等（由于对不精确性和偏倚风险的担忧而调低评级）；死亡率方面：低（由于严重 强烈建议使用 我们建议使用奈玛特韦-利托那韦治疗（强烈建议）。 • 关于识别风险最高患者的帮助，参阅第6.1节。 • 有几种治疗方案可供选择：参见 决策支持工具，该工具列出了奈玛特韦-利托那韦、莫努匹拉韦、瑞德西韦和单克隆抗体 的利弊。 • GDG得出结论，奈玛特韦-利托那韦是一种更优的选择，因为它在预防住院方面可能比替代药物具有更大的疗效，对其危 害的担忧少于莫努匹拉韦；并且比静脉注射瑞德西韦和抗体更容易给药。 • 赞成使用的强烈建议不适用于孕妇、儿童或可能发生危险药物相互作用的人群（许多药物与奈玛特韦-利托那韦有相互作 用，见“作用机制”）。 • 奈玛特韦-利托那韦应在症状出现后尽快（最好在5天内）给药。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 21 of 119 的不精确性和间接性而调低评级），导致停药的不良反应方面：高。我们没有对腹泻和味觉障碍证据的确定性进行评分。 现有基于实证开发的用以确定患者住院风险的风险预测工具存在局限性，这是导致GDG调低证据确定性等级的间接性的主要 来源(31)。 价值观和偏好 GDG应用商定的价值观和偏好（见第7节）推断，几乎所有住院风险较高的知情患者都会选择使用奈玛特韦-利托那韦。 资源和其他考虑因素 可接受性和可行性 并非所有愿意接受该治疗选项的人都能获得奈玛特韦-利托那韦。这强化了奈玛特韦-利托那韦应仅用于较高风险人群的观点。 出于成本和可获性原因，低收入和中等收入国家（LMICs）面临的可及性障碍可能是巨大的。在出现症状的最初5天，社会经 济的弱势群体获得服务的机会往往较少（包括诊断测试和治疗），因而少有机会获取干预措施。因此，如果由风险较高的患者接 受干预，可能会加剧卫生不公平。重要的是，各国应将COVID-19临床护理路径纳入可为COVID-19非重症患者提供护理的卫生系 统部分（即初级保健、社区护理环境）。 这些建议应激励所有可能的机制参与改善此干预措施的全球可及性。例如，2021年12月17日，世卫组织发布了第7次邀请，请 COVID-19疗法制造商向世卫组织预认证部门提交产品评估意向书(EOI)。如果该评估表明某一产品及其相应的生产（和临床）地 点符合世卫组织建议的标准，则该产品将被列入联合国组织和其他机构认为可采购的医药产品清单。各国可根据可用资源制定自 己的指南，并相应地确定治疗方案的优先次序。 获得SARS-CoV-2诊断方法：由于本建议涉及在理想状态下于症状出现后5天内使用奈玛特韦-利托那韦进行治疗，因此提高诊 断检测方法的可及性并确保其正确使用对于实施至关重要。因此，需要提供并使用适当的SARS-CoV-2诊断检测，以改善获得药物 的机会，特别是那些针对疾病早期阶段的药物。适当使用抗原检测等快速诊断检测可以改善社区和初级卫生保健机构的早期诊 断。然而，卫生保健系统必须具备选择和实施快速检测方面的专门知识，从而选择最适合其环境的检测方法。 理由 中等确定性证据表明住院治疗的相对风险显著降低，高确定性证据显示未有需要停药的不良反应，这推动了对住院风险较高 的个体使用该药的强烈建议。与未接受奈玛特韦-利托那韦治疗的患者相比，这些个体的住院绝对风险可能显著降低。 替代或联合疗法 GDG此前曾有条件建议对最高风险的非重症人群使用莫努匹拉韦（见第6.6节），并在本次指南更新中有条件建议使用瑞德西 韦（见第6.5节）。通过对较高风险和最高风险患者的间接比较发现，与莫努匹拉韦相比，奈玛特韦-利托那韦可能减少住院治疗 （低确定性）；然而与瑞德西韦相比，几乎没有发现差异（低确定性）。由于缺乏直接数据比较，且间接比较的置信度为低确定 性，GDG选择不对药物之间的比较做出建议，而是指出奈玛特韦-利托那韦的疗效与标准治疗相比可能更优（中等确定性），然后 基于实际问题（如给药容易度和风险状况）做出最终选择。 没有证据支持联合抗病毒疗法；因此，GDG建议不要这样做。 适用性 目前尚不确定本建议对儿童、哺乳期妇女和孕妇的适用性，因为所纳入的随机对照试验所招募的均为非妊娠成年人。GDG的 结论是，不应向患有COVID-19的儿童、哺乳期妇女或孕妇提供奈玛特韦-利托那韦。 临床问题/PICO 对象：非重症 COVID-19 患者 干预：奈玛特韦-利托那韦 对照：不使用奈玛特韦-利托那韦 摘要 关于奈玛特韦-利托那韦的LNMA参考了两项随机对照试验(EPIC-SR 和HR)，共招募了3100名门诊非重症患者。两项随机对照试 验已登记；其中一项发表在同行评审的期刊上(30)。纳入的研究均未招募儿童或孕妇。此表显示了随机对照试验的特征。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，奈玛特韦-利 托那韦与标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息 (3)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 22 of 119 计划的亚组分析受到可用数据的限制，但在血清学状态和年龄（未招募儿童）方面没有发现可信的亚组效应。由于所有患者均 未接种疫苗，并且在症状出现后5天内被随机分配，并且没有患者接受治疗性联合干预，这些亚组分析无法进行。 结局 时间表 研究结果和衡量标准 对照 不使用奈玛特韦- 利托那韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 优势比 0.04 (95%置信区间 0 - 0.67) 基于2项研究中 3100名参与者的 数据。 （随机对照） 6 每1000人 0 1000人 低 由于严重的 不精确性和 间接性1 奈玛特韦-利托那韦 可能对死亡率 有很小的影响 差异：每1000人减少6例 ( 95%置信区间减少6例 — 减少2例 ） 机械通气 尚无数据 奈玛特韦-利托那韦的 作用未知 住院 试验中的风险 优势比 0.15 (95%置信区间 0.06 - 0.38) 基于2项研究中 3078名参与者的 数据。(随机对 照） 35 每1000人 5 每 1000 人 中等 由于对偏倚风险和 不精确性的担忧2 奈玛特韦-利托那韦 很可能减少住院治疗 差异：每1000人减少30例 （95%置信区间 减少33例 — 减少21例） 住院 较高风险 优势比 0.15 (95%置信区间 0.06 - 0.38) 基于2项研究中 3078名参与者的 数据。 （随机对照） 60 每1000人 9 每 1000 人 中等 由于对偏倚风险和 不精确性的担忧3 奈玛特韦-利托那韦 很可能减少住院治疗 差异：每1000人减少51例 （95%置信区间减少56例 — 减少36例） 住院 最高风险 优势比0.15 (95%置信区间 0.06 - 0.38) 基于2项研究中 3078名参与者的 数据。 （随机对照） 100 每1000人 16 每1000人 中等 由于对偏倚风险和 不精确性的担忧4 奈玛特韦-利托那韦 很可能减少住院治疗 差异：每1000人减少84例 （95%置信区间减少93例 — 减少59例） 导致停药的 不良反应 优势比0.48 (95%置信区间 0.29 - 0.8) 基于1项研究中 2246名参与者的 数据。 （随机对照） 0 每1000人 0 每1000人 高 奈玛特韦-利托那韦 几乎没有导致停药的 不良反应风险 差异：每1000人减少0例 （95%置信区间减少0例 — 减少0例） 机械通气 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 间接性：严重。一些患者的死亡风险可能要高得多。奈玛特韦-利托那韦很可能降低这些患者的死亡率。不精确性：严 重。只有12个事件（都在安慰剂组中）；而且只有一项研究。 2. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 3. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 4. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 23 of 119 临床问题/PICO 对象：非重症 COVID-19患者 干预：奈玛特韦-利托那韦 对照：莫努匹拉韦 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 优势比0 （CI 95% 0 - 0.29） （随机对照） 0 每1000人 0 每1000人 中等 由于严重的 间接性1 死亡率很可能几乎 没有差异 差异：每1000人减少0例 （95%置信区间减少0例-减少0例） 机械通气 尚无数据 奈玛特韦-利托那韦的 作用未知 住院 试验中的风险 优势比0.29 （95%置信区间 0.1 - 0.88） （随机对照） 19 每1000 人 6 每1000 人 低 由于偏倚风险和 不精确性2 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少13例 （95%置信区间减少17例—减少2例） 住院 最高风险 优势比 0.29 （95%置信区间 0.1 - 0.88） （随机对照） 57 每1000人 17 每1000人 低 由于偏倚风险和 不精确性3 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少40例 （95%置信区间减少51例—减少6例 ） 住院 较高风险 优势比 0.29 （95%置信区间 0.1 - 0.88） （随机对照） 33 每1000人 17 每1000人 低 由于偏倚风险和 不精确性4 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少40例 （95%置信区间 减少51例—减少6例 ） 导致停药的 不良反应 0 每1000人 0 每1000人 高 在导致停药的不良 反应风险方面几乎 没有差异 差异：每1000人减少0例 （95%置信区间减少0例-减少0例） 机械通气 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。 2. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 3. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 4. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 24 of 119 临床问题/PICO 对象：非重症COVID-19患者 干预：瑞德西韦 对照：奈玛特韦-利托那韦 结局 时间表 研究结果和衡量标准 对照 奈玛特韦-利托那韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天内 0 每1000人 3 每1000人 非常低 由于存在严重的 偏倚风险、间接性和 不精确性1 对死亡率的影响 不确定 差异：每1000人增加3例 增加2例 - 增加5例 机械通气 尚无数据 对机械通气的 作用未知 住院 试验中的风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 6 每1000人 9 每1000人 由于严重的偏倚 风险和不精确性2 住院治疗方面可能 几乎没有差异 差异：每1000人增加3例 （95%置信区间减少4例—增加38例） 住院 较高风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 9 每1000人 15 每1000人 低 由于严重的偏倚 风险和不精确性3 住院治疗方面可能 几乎没有差异 差异：每1000人增加6例 （95%置信区间减少6例—增加55例） 住院 最高风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 16 每1000人 26 每1000人 低 由于严重的偏倚 风险和不精确性4 住院治疗方面可能 几乎没有差异 差异：每1000人增加10例 （95%置信区间减少11例—增加94例） 导致停药的 不良反应 0 每1000人 9 每1000人 非常低 由于非常严重的 不精确性、严重的 偏倚风险、严重的 间接性和非常 严重的偏倚风险5 对导致停药的不良 反应的影响 尚不确定 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 偏倚风险：严重。间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。不精确 性：严重。事件很少：瑞德西韦与对照组发生50个事件，莫努匹拉韦与对照组发生11个事件。 2. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 3. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 4. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 5. 偏倚风险：非常严重。间接性：严重。不精确性：非常严重。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 25 of 119 用于低住院风险的非重症COVID-19患者 实用信息 途径、剂量和持续时间：其他考虑因素参见实用问题摘要。 在考虑对任何患者使用奈玛特韦-利托那韦时，临床医生需要认真考虑药物相互作用。在此方面，利物浦COVID-19药物相互 作用检查工具可能有用(28)。 决策证据 利弊 在COVID-19非重症患者中，奈玛特韦-利托那韦很可能减少住院治疗。然而在低风险患者中，绝对获益非常小，因而对大多 数患者而言不太可能重要。奈玛特韦-利托那韦很可能对死亡率几乎没有影响。关于症状消除所需时间（与低住院风险患者高度相 关），研究没有报告数据。然而，EPIC-SR确实报告了一个非常密切相关的结果：达到连续4天轻度或无症状所需时间。对于该分 析，奈玛特韦-利托那韦的中位数时间为13.0（95%置信区间12至15）天，安慰剂的中位时间为13.0（95%置信区间11至14）天 （p=0.47）。使用奈玛特韦-利托那韦治疗不会增加导致停药的不良反应的概率，但与安慰剂相比，使用奈玛特韦-利托那韦治疗发 生腹泻和味觉障碍的频率更高。 证据的确定性 关于奈玛特韦 -利托那韦的证据摘要参考了LNMA研究纳入的两项试验（EPIC-SR和EPIC-HR），共有3100名参与者 (1)(29)(30)。 证据的确定性被评为：减少住院方面：中等（由于担忧严重的不精确性和偏倚风险而调低评级）；死亡率方面：低（由于严 重的不精确性和间接性而调低评级），导致停药的不良反应方面：高。我们没有对腹泻和味觉障碍的证据确定性进行评分。 价值观和偏好 GDG相信，大多数低风险患者不愿使用有证据显示对其认为重要的结局影响高度不确定的药物。这一考虑因素对于缩短症状 持续时间尤其重要，对此，我们没有直接证据支持奈玛特韦-利托那韦的积极影响。 资源和其他考虑因素 并非所有愿意接受该治疗选项的人都能获得奈玛特韦-利托那韦。这强化了奈玛特韦-利托那韦应仅用于最高风险人群的观点。 理由 大多数感染COVID-19的患者的住院风险非常低（低于1%），死亡风险极小。这些患者使用奈玛特韦-利托那韦将得到的益处 微不足道。该小组推断，大多数此类患者对使用该药物以获得这些微不足道的好处不感兴趣。因此对于大多数患者来说，也至少 需要一个风险因素（如果不是多个风险因素的组合）才能构成足够的风险（因而可获得奈玛特韦-利托那韦的足够益处），从而让 使用奈玛特韦-利托那韦成为具有吸引力的选项。在低收入地区尤其如此，那里的资源约束和可行性问题将让使用奈玛特韦-利托那 韦的吸引力下降。 然而，GDG知道，可能有相当数量的人高度重视住院风险的微小降低，因此会选择使用奈玛特韦-利托那韦；因此，做出的是 有条件建议，而非强烈建议。 有条件建议不使用 新增 我们建议不使用奈玛特韦-利托那韦。（有条件建议不使用） • 在GDG的评估中，只有少数低风险患者会选择使用奈玛特韦-利托那韦。 • 抗病毒药物试验纳入了具有某些住院风险因素的患者，导致GDG用于制定建议的基线风险为3%。一般人群的住院风险可 能更低。 • 临床医生不应考虑对孕妇、儿童或可能存在危险药物相互作用的患者使用奈玛特韦-利托那韦（注意：许多药物与奈玛特 韦-利托那韦发生相互作用）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 26 of 119 临床问题/PICO 对象：非重症COVID-19患者 干预：奈玛特韦-利托那韦 对照：不使用奈玛特韦-利托那韦 摘要 关于奈玛特韦-利托那韦的LNMA参考了两项随机对照试验(EPIC-SR和HR)，共招募了3100名门诊非重症患者。两项随机对照试 验已登记；其中一项发表在同行评审的期刊上(30)。纳入的研究均未招募儿童或孕妇。此表显示了随机对照试验的特征。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，奈玛特韦-利 托那韦与标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息(3)。 计划的亚组分析受到可用数据的限制，但没有发现在血清学状态和年龄（未招募儿童）方面存在可信的亚组效应。由于所有患 者均未接种疫苗，并且在症状出现后5天内被随机分配，并且没有患者接受治疗性联合干预，这些亚组分析无法进行。 结局 时间表 研究结果和衡量标准 对照 不使用奈玛特韦- 利托那韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 优势比0.04 （95%置信区间 0 - 0.67） 基于2项研究中 3100名参与者的 数据。 （随机对照） 6 每1000人 0 每1000人 低 由于严重的 不精确性和 间接性1 奈玛特韦-利托那韦 可能对死亡率有很 小的影响 差异：每1000人减少6例 （95%置信区间减少6例 — 减少2例） 机械通气 尚无数据 奈玛特韦-利托那韦的 作用未知 住院 试验中的风险 优势比0.15 （95%置信区间 0.06 - 0.38） 基于2项研究中 3078名参与者的 数据。 （随机对照） 35 每1000人 5 每1000 人 中等 由于对偏倚 风险和 不精确性的 担忧2 奈玛特韦-利托那韦很 可能减少 住院治疗 差异：每1000人减少30例 （95%置信区间减少33例 — 减少21例） 住院 较高风险 优势比0.15 （95%置信区间 0.06 - 0.38） 基于2项研究中 3078名参与者的 数据。 （随机对照） 60 每1000人 9 每1000 人 中等 由于对偏倚 风险和 不精确性的 担忧3 奈玛特韦-利托那韦很 可能减少 住院治疗 差异：每1000人减少51例 （95%置信区间减少56例 — 减少36例） 住院 最高风险 优势比0.15 （95%置信区间 0.06 - 0.38） 基于2项研究中 3078名参与者的 数据。 （随机对照） 100 每1000人 16 每1000人 中等 由于对偏倚 风险和 不精确性的 担忧4 奈玛特韦-利托那韦很 可能减少 住院治疗 差异：每1000人84例 （95%置信区间减少93例 — 减少59例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 27 of 119 结局 时间表 研究结果和衡量标准 对照 不使用奈玛特韦- 利托那韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 导致停药的 不良反应 优势比0.48 （95%置信区间 0.29 - 0.8） 基于1项研究中 2246名参与者的 数据。 （随机对照） 0 每1000人 0 每1000人 高 奈玛特韦-利托那韦几 乎没有导致 停药的不良反应 风险 差异：每1000人减少0例 （95%置信区间减少0例-减少0例） 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 间接性：严重。一些患者的死亡风险可能要高得多。奈玛特韦-利托那韦可能降低这些患者的死亡率。不精确性：严重。 只有12个事件（都在安慰剂组中）；而且只有一项研究。 2. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 3. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 4. 偏倚风险：严重。该研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 临床问题/PICO 对象：非重症COVID-19患者 干预：奈玛特韦-利托那韦 对照：莫努匹拉韦 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 优势比0 （CI 95% 0 - 0.29） （随机对照） 0 每1000人 0 每1000人 中等 由于严重的 间接性1 死亡率很可能几乎 没有差异 差异：每1000人减少0例 （95%置信区间减少0例 — 减少0例） 机械通气 尚无数据 奈玛特韦-利托那韦的 作用未知 住院 试验中的风险 优势比0.29 （95%置信区间 0.1 - 0.88） （随机对照） 19 每1000人 6 每1000人 低 由于偏倚风险 和不精确性2 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少13例 （95%置信区间减少17例 — 减少2例） 住院 最高风险 优势比0.29 （95%置信区间 0.1 - 0.88） （随机对照） 57 每1000人 17 每1000人 低 由于偏倚风险 和不精确性3 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少40例 （95%置信区间减少51例 — 减少6例） 住院 较高风险 优势比0.29 （95%置信区间 0.1 - 0.88） （随机对照） 33 每1000人 17 每1000人 低 由于偏倚风险 和不精确性4 奈玛特韦-利托那韦 可能比莫努匹拉韦 更能减少住院治疗 差异：每1000人减少40例 （95%置信区间减少51例 — 减少6例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 28 of 119 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 奈玛特韦/利托那韦 证据的确定性 （证据质量） 纯文本摘要 导致停药的 不良反应 0 每1000人 0 每1000人 高 在导致停药的不良 反应风险方面几乎 没有差异 差异：每1000人减少0例 （95%置信区间 减少0例 — 减少0例） 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。 2. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 3. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 4. 偏倚风险：严重。奈玛特韦-利托那韦的研究被提前停止以求益处。不精确性：严重。总样本量不满足最优信息样本量。 临床问题/PICO 对象：非重症 COVID-19患者 干预：瑞德西韦 对照：奈玛特韦-利托那韦 结局 时间表 研究结果和衡量标准 对照 奈玛特韦-利托那韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 0 每1000人 3 每1000人 非常低 由于存在严重的 偏倚风险、间接性 和不精确性1 对死亡率的影响 不确定 差异：每1000人增加3例 增加2例 — 增加5例 机械通气 尚无数据 对机械通气的 作用未知 住院 试验中的风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 6 每1000人 9 每1000人 低 由于严重的偏倚 风险和不精确性2 住院治疗方面可能 几乎没有差异 差异：每1000人增加3例 （95%置信区间减少4例 — 增加38例） 住院 较高风险 优比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 9 每1000人 15 每 1000人 低 由于严重的偏倚 风险和不精确性3 住院治疗方面可能 几乎没有差异 差异：每1000人增加6例 （95%置信区间减少6例—增加55例） 住院 最高风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 16 每1000人 26 每1000人 低 由于严重的偏倚 风险和不精确性4 住院治疗方面可能 几乎没有差异 差异：每1000人增加10例 （95%置信区间减少11例 — 增加94例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 29 of 119 结局 时间表 研究结果和衡量标准 对照 奈玛特韦-利托那韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 导致停药的 不良反应 0 每1000人 9 每1000人 非常低 由于非常严重的 不精确性、严重的 偏倚风险、严重的 间接性和非常 严重的偏倚风险5 对导致停药的不良 反应的影响 尚不确定 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 1. 偏倚风险：严重。间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。不精确 性：严重。事件很少：瑞德西韦与对照组发生50个事件，莫努匹拉韦与对照组发生11个事件。 2. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 3. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 4. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 5. 偏倚风险：非常严重。间接性：严重。不精确性：非常严重。 6.4.1. 作用机制 奈玛特韦抑制SARS-CoV-2蛋白酶（3CLpro），从而防止病毒多蛋白的分裂，而病毒蛋白必须分裂才能发挥功能(32)。抑制蛋 白酶使病毒无法复制。与奈玛特韦联合给药的利托那韦是一种艾滋病毒蛋白酶抑制剂，在此用于增强奈玛特韦的药代动力学，但 本身不发挥任何直接的抗病毒活性(33)。因此，该联合用药应视作抗病毒单药疗法。奈玛特韦为静脉注射前体药物（lufotrelvir； PF-07304814）的可口服相似物。该药物最初是为SARS-CoV开发的，后被转用于SARS-CoV-2。 奈玛特韦在分化的正常人支气管上皮细胞中表现出对SARS-CoV-2的抗病毒活性，EC50为0.06微摩尔，EC90为0.18微摩尔 (33)。在健康志愿者中，奈玛特韦的血浆最大浓度为2210 ng/mL，在给与300/100mg剂量的奈玛特韦-利托那韦后半衰期为6小时， 并且在第2天达到稳态药代动力学(34)（EC90为0.18微摩尔相当于约90ng/mL）。高剂量（300mg/kg）未加强的奈玛特韦在小鼠中 对适应小鼠的SARS-CoV-2具有活性，但最大浓度高于健康人类志愿者在300/100mg剂量时达到的浓度(33)。高剂量（250mg/kg） 未加强的奈玛特韦对感染SARS-CoV-2的叙利亚金黄地鼠也有疗效，但没有关于该物种药代动力学数据(35)。基于奥密克戎的基因 组序列，似乎没有丧失活性的分子学基础。奈玛特韦在体外保持对奥密克戎BA.1的活性(36)，但目前暂无体内数据。 尚需更多数据才能确定奈玛特韦出现耐药性的速度。在蛋白酶序列中引入的单个氨基酸变化可使奈玛特韦的活性降低23.6至 39倍(34)。小鼠肝炎病毒（用作β冠状病毒替代物）在体外环境的选择性压力下获得了几个突变，使奈玛特韦活性降低了4至91倍 (34)。临床试验中描述了两种氨基替代，其中一种不影响奈玛特韦的活性。 通过其对代谢和清除的影响，利托那韦引起许多药物之间的相互作用，需要仔细考虑。COVID-19所需的疗程短，可能使药物 相互作用相比艾滋病毒更易管理，但每日两次给药意味着该利托那韦剂量是大多数现代抗逆转录病毒方案剂量的两倍。利托那韦 对代谢的影响也可能长于给药时长数天。利物浦COVID-19药物相互作用检查器可能是管理与奈玛特韦-利托那韦的药物相互作用 的宝贵工具(28)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 30 of 119 6.5. 瑞德西韦（2022年4月22日发布） 信息栏 2020年11月20日最早提出了有条件建议，建议无论疾病严重程度如何，都不要对COVID-19患者使用瑞德西韦。这是基于当时 可用的四项随机对照试验（包括因COVID-19住院的7333名参与者）的数据。在该指南的第十版更新中，提出了一项将瑞德西韦用 于非重症患者的新建议，对COVID-19重症或危重症患者的建议正在审查中，即将更新。 本第十一版指南没有对瑞德西韦的建议进行修订。 用于住院风险最高的非重症COVID-19患者 实用信息 途径、剂量和持续时间：三个实用问题摘要提供了其他考虑因素（瑞德西韦用于治疗COVID-19，瑞德西韦用于治疗COVID- 19的给药，接受瑞德西韦治疗COVID-19的患者的安全性和监测）。以下是关键要点的简明摘要： • 根据本建议参考的大型试验所评估的方案，瑞德西韦的推荐剂量为每日1剂，连续3天静脉输注。瑞德西韦为第1天静脉 给药200mg，之后在第2天和第3天静脉给药100mg。 • 应在病程中尽早给药。在纳入的研究中，瑞德西韦在发病后7天内给药。 • 输注后对患者进行短时监测可能是合理的。进行输液的任何卫生保健工作者都应遵循推荐的门诊环境感染预防和控制建 议。 • 对患有严重肝脏或肾脏疾病的患者，应谨慎使用瑞德西韦。 • GDG指出，试验没有招募12岁或以下、体重低于40公斤的儿童，因此建议不在这些儿童中使用。 • 此外，这些试验没有招募孕妇或哺乳期妇女。孕妇应与其卫生保健提供者讨论此疗法潜在的益处是否足以值得其对母亲 和胎儿的潜在风险，从而决定是否使用此疗法（见研究证据和世卫组织信息表）。 决策证据 利弊 在COVID-19非重症患者中，瑞德西韦很可能会减少住院，而可能对死亡率几乎没有影响。瑞德西韦对机械通气和症状消除时 间的影响非常不确定。治疗很可能不会增加导致停药的严重不良反应的概率。 益处和潜在危害之间的权衡倾向于支持治疗，但仅限于最高风险组。这是因为瑞德西韦针对住院治疗的绝对益处取决于特定 患者的预后。GDG定义了住院概率绝对减少6%的阈值，以代表大多数患者认为的重要益处。 瑞德西韦将在住院风险最高（基线风险高于10%）的患者中发挥这种益处，例如由于未接种疫苗而进一步增加了风险的老年 人或免疫缺陷和/或慢性病患者。在风险最高（基线风险高于10%）的患者中使用瑞德西韦的有条件建议反映了这一阈值：每1000 名患者减少73例住院。 在没有公开报告的或由研究者提供的亚组数据的情况下，未能在瑞德西韦与标准治疗之间开展年龄、症状出现时间和疾病严 重程度方面的计划亚组分析。有八名儿童（12岁或以上）参加了PINETREE试验（37）；然而，没有出现死亡或住院病例。 有条件建议使用 我们建议使用瑞德西韦治疗（有条件建议使用）。 • 关于识别最高住院风险患者的帮助，参阅第6.1节。 • 有几种治疗方案可供选择：参见决策支持工具，该工具列出了奈玛特韦-利托那韦、莫努匹拉韦、瑞德西韦和单克隆抗体 的利弊。 • GDG得出结论，奈玛特韦-利托那韦是一种更优的选择，因为它在预防住院方面可能比替代药物更加有效，有关其危害的 担忧少于莫努匹拉韦；并且比静脉注射瑞德西韦和抗体更容易给药。 • 瑞德西韦应在症状出现后尽快（最好在7天内）给药。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 31 of 119 证据的确定性 证据摘要参考了纳入LNMA的5项试验，包含2709名参与者，其中一项试验为住院结局提供了信息(1) (37)。 证据的确定性被评为：减少住院方面，中等（由于严重的不精确性）；死亡率方面，低（由于严重的不精确性和间接性）； 机械通气方面，非常低（由于极为严重的不精确性和严重的偏倚风险）；以及，导致停药的不良反应方面，中等。 现有基于实证开发的用以确定患者住院风险的风险预测工具存在局限性，这是导致GDG调低证据确定性等级的间接性原因的 主要来源。(18) (31)详情参见6.1节。 价值观和偏好 GDG应用商定的价值观和偏好（见第7节）推断，几乎所有充分知情的低住院风险患者都会拒绝使用瑞德西韦，而只有那些风 险最高的患者会选择接受治疗。 资源和其他考虑因素 可接受性和可行性 瑞德西韦的给药是每日一次静脉输注，连续 3 天，这对希望避免住院的门诊患者造成可行性方面的困难。此外，并非所有愿 意接受该治疗选项的人都能获得瑞德西韦。这强化了瑞德西韦应仅用于最高风险人群的观点。 令人关切的是，由于成本、可行性和可得性的原因，低收入和中等收入国家(LMICs)在获取此项治疗方面面临障碍(38)。在低 收入和中等收入国家中，就瑞德西韦进行共同决策、并就其利弊开展沟通方面的挑战也可能增加。例如，在出现症状的最初7天， 社会经济的弱势群体往往较少能获得服务（包括诊断测试和治疗），因而少有机会获取干预措施。因此，如果由风险最高的患者 接受干预，可能会加剧卫生不公平。重要的是，各国应将COVID-19临床护理路径纳入卫生系统中可为COVID-19非重症患者提供 护理的部分（即初级保健、社区护理环境）。 这些建议应激励所有可能的机制参与改善此干预措施的全球可及性。例如，2021年12月17日，世卫组织发布了第8次邀请，请 COVID-19疗法制造商向世卫组织预认证部门提交产品评估意向书(EOI)。如果该评估表明某一产品及其相应的生产（和临床）地 点符合世卫组织建议的标准，则该产品将被列入联合国组织和其他机构认为可采购的医药产品清单。各国可根据可用资源制定自 己的指南，并相应地确定治疗方案的优先次序。 获得SARS-CoV-2诊断方法：由于本建议强调了有必要在症状出现后7天内使用瑞德西韦进行治疗，因此提高诊断检测方法的 可及性并确保其正确使用至关重要。因此，需要提供和使用可靠和及时的SARS-CoV-2诊断检测（包括使用核酸扩增检测 （NAAT）和基于抗原的快速检测（Ag-RDTs））来改善药物的可及性，特别是那些针对疾病早期阶段的药物。个人和训练有素 的专业人员适当地使用抗原快速诊断检测可以改善早期诊断和早期获得临床护理的机会，特别是在社区和初级卫生保健环境中。 国家规划应优化其检测系统，以反映当地流行病学、应对目标、可用资源和人群需求。 理由 当基于证据有条件建议对COVID-19非重症患者使用瑞德西韦时，GDG强调了该药物在减少住院方面的益处，同时几乎没有严 重的不良反应。对给药的可行性和复杂性也给予了认真考虑，因而建议仅在风险最高的患者中使用。风险最高人群的典型特征包 括，因未接种疫苗而进一步增加风险的老年人或免疫缺陷和/或慢性疾病患者。 成本和可及性是重要的考虑因素，GDG认识到这一建议可能会加剧卫生不公平现象。GDG预期患者们的价值观和偏好不会有 重大差异（参见决策证据）。 替代或联合疗法 GDG此前曾有条件建议对最高风险的非重症人群使用莫努匹拉韦，在本指南中强烈建议使用奈玛特韦-利托那韦（见第6.2 节），并且有条件建议不在低风险非重症人群中使用奈玛特韦-利托那韦。通过对较高风险和最高风险患者的间接比较发现，与莫 努匹拉韦相比，瑞德西韦可能减少住院治疗（低确定性）；而其与奈玛特韦-利托那韦相比，发现几乎没有差异（低确定性）。由 于缺乏直接数据，且间接比较的置信度为低确定性，GDG选择不对药物之间的比较做出建议，而是指出奈玛特韦-利托那韦的疗效 与标准治疗相比可能更优，最终选择基于实际问题（如给药和潜在的药物之间相互作用）做出。 没有证据支持联合抗病毒疗法；因此，GDG建议不要这样做。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 32 of 119 适用性 纳入的试验中只有一项包括了儿童（12岁及以上），而且数量极少；因此，本建议对儿童的适用性仍然不确定。在对孕妇或 哺乳期妇女使用瑞德西韦方面也存在不确定性。孕妇应与其卫生保健提供者讨论此疗法潜在的益处是否足以值得其对母亲和胎儿 的潜在风险，从而决定是否使用此疗法（参见“研究证据”和“实用信息标签”）。 GDG还担心该药物是否会对奥密克戎 BA.1或BA.2等新出现的需要关注的变异株保持疗效。需要监测对瑞德西韦易感性降低的 SARS-CoV-2毒株，并进一步研究联合疗法在重度免疫功能低下患者中的作用。在获得更多数据之前，我们没有理由相信该药针对 已知变异株的活性会下降。 临床问题/PICO 对象：非重症 COVID-19患者 干预：瑞德西韦 对照：奈玛特韦-利托那韦 结局 时间表 研究结果和衡量标准 对照 奈玛特韦-利托那韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 28 天 0 每1000人 3 每1000人 非常低 由于存在严重的 偏倚风险、间接性 和不精确性1 对死亡率的影响 不确定 差异：每1000人增加3例 增加2例 — 增加5例 机械通气 尚无数据 对机械通气的作用 未知 住院 试验中的风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 6 每1000人 9 每1000人 低 由于严重的偏倚 风险和不精确性2 住院治疗方面可能 几乎没有差异 差异：每1000人增加3例 （95%置信区间减少4例 — 增加38例） 住院 较高风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 9 每1000人 15 每1000人 低 由于严重的偏倚 风险和不精确性3 住院治疗方面可能 几乎没有差异 差异：每1000人增加6例 (95%置信区间减少6例 — 增加55例) 住院 最高风险 优势比1.64 （95%置信区间 0.33 - 7.57） （随机对照） 16 每1000人 26 每1000人 低 由于严重的偏倚 风险和不精确性4 住院治疗方面可能 几乎没有差异 差异：每1000人增加10例 (95%置信区间减少11例 — 增加94例) 导致停药的 不良反应 0 每1000人 9 每1000人 非常低 由于非常严重的 不精确性、严重的 偏倚风险、严重的 间接性和非常严重的 偏倚风险5 对导致停药的 不良反应的影响 尚不确定 症状消除时间 尚无数据 奈玛特韦-利托那韦的 作用未知 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 33 of 119 1. 偏倚风险：严重。间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。不精确性： 严重。事件很少：瑞德西韦与对照组发生50个事件，莫努匹拉韦与对照组发生11个事件。 2. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 3. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 4. 偏倚风险：严重。EPIC-HR的研究被提前停止以求益处。不精确性：严重。可信区间不包括差异和重要危害。 5. 偏倚风险：非常严重。间接性：严重。不精确性：非常严重。 临床问题/PICO 对象：非重症COVID-19患者 干预：瑞德西韦 对照：不使用瑞德西韦 摘要 关于瑞德西韦的LNMA参考了五项随机对照试验，共招募了2731名门诊非重症患者。2710名患者的数据可用。全部随机对照试 验已登记；其中四项发表在同行评审期刊上(15)(37)(39)(40)。其中一项纳入的研究招募了12岁及以上的儿童；没有一项研究包括孕 妇。此表显示了随机对照试验的特征。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，瑞德西韦与 标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息(3)。 在非重症亚组中，PINETREE试验是唯一一项报告了亚组的研究(37)。计划的亚组分析受到可用数据的限制，但没有发现在血 清学状态和年龄方面存在可信的亚组效应。由于所有患者均未接种疫苗，在症状出现后7天内随机分配，并且没有接受治疗性联合 干预，因而无法进行这些亚组分析。值得注意的是，在年龄方面，PINETREE试验中1.4% (n=8)的参与者年龄在12至18岁之间，没有 出现死亡或住院病例；60岁以上对比60岁及以下患者，未见亚组效应（p=0.78）。 结局 时间表 研究结果和衡量标准 对照 不使用瑞德西韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.68 （95%置信区间 0.39 - 1.21） 基于5项研究中 2709 名参与者的 数据。 （随机对照） 6 每1000人 4 每1000人 低 由于严重的间接性 和不精确性1 瑞德西韦很可能 对死亡率几乎 没有影响 差异：每1000人减少2例 减少4例 — 增加1例 机械通气 优势比0.42 （95%置信区间 0.08 - 1.96） 基于 2 项研究中 261 名参与者的 数据。 （随机对照） 8 每 1000人 3 每1000人 非常低 由于严重的 不精确性和严重的 间接性2 瑞德西韦对机械 通气的影响不确定 差异：每1000人减少5例 （95%置信区间减少7例 — 增加8例） 住院 试验中的风险 优势比0.25 （95%置信区间 0.06 - 0.88） 基于1项研究中 562名参与者的 数据。 （随机对照） 35 每1000人 9 每1000 人 中等 由于严重的 不精确性3 瑞德西韦很可能 减少住院治疗 差异：每1000人减少26例 （95%置信区间减少33例 — 减少4例） 住院 较高风险 优势比0.25 （95%置信区间 0.06 - 0.88） 基于1项研究中 562名参与者的数据。 （随机对照） 60 每1000人 16 每1000人 中等 由于严重的 不精确性4 瑞德西韦很可能 减少住院治疗 差异：每1000人减少44例 （95%置信区间减少56例 — 减少7例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 34 of 119 结局 时间表 研究结果和衡量标准 对照 不使用瑞德西韦 干预 瑞德西韦 证据的确定性 （证据质量） 纯文本摘要 住院 最高风险 优势比0.25 （95%置信区间 0.06 - 0.88） 基于1项研究中 562名参与者的数据。 （随机对照） 100 每1000人 27 每1000人 中等 由于严重的 不精确性5 瑞德西韦很可能 减少住院治疗 差异：每1000人减少73例 （95%置信区间减少93例 — 减少11例） 导致停药的 不良反应 基于4项研究1379名 参与者的数据。 （随机对照） 0 每1000人 9 每1000人 中等 由于严重的 不精确性6 在导致停药的 不良反应方面 很可能几乎 没有差异 差异：每1000人增加9例 (95%置信区间减少3例 — 增加21例) 症状消除时间 越低越好 基于1项研究中138名 参与者的数据。 （随机对照） 9 天（中位数） 7.2 天（均值） 非常低 由于极其严重的 不精确性7 瑞德西韦对症状 消除的影响不确定 差异：平均差减少1.8 （95%置信区间减少5.7 — 增加3.5） 1. 间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。不精确性：严重。不满足最 优信息样本量；事件很少（总共 50 个事件）。 2. 间接性：严重。一些患者的机械通气风险可能要高得多。这些患者在机械通气方面可能存在重要差异。不精确性：非常 严重。可信区间包括重要益处和重要危害。不满足最优信息样本量；事件很少（总共 11 个）。 3. 不精确性：严重。总样本量不满足最优信息样本量。事件很少（总共 23 个事件）。 4. 不精确性：严重。总样本量不满足最优信息样本量。事件很少（总共 23 个事件）。 5. 不精确性：严重。总样本量不满足最优信息样本量。事件很少（总共 23 个事件）。 6. 不精确性：严重。 7. 不精确性：极为严重。 临床问题/PICO 对象：非重症 COVID-19 患者 干预：瑞德西韦 对照：莫努匹拉韦 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 瑞德西韦 证据的确定性 (证据质量) 纯文本摘要 死亡率 优势比6.55 （95%置信区间 1.3 - 53.23） （随机对照） 0 每1000人 0 每1000人 低 由于严重的间接性 和不精确性1 死亡率可能几乎 没有差异 差异：每1000人减少0例 减少0例-减少0例 机械通气 优势比1.08 （95%置信区间 0.12 - 9） （随机对照） 8 每1000人 9 每 1000人 低 由于严重的偏倚 风险和间接性2 机械通气方面可能 几乎没有差异 差异：每1000人增加1例 (95%置信区间减少13例—增加16例) 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 35 of 119 结局 时间表 研究结果和衡量标准 对照 莫努匹拉韦 干预 瑞德西韦 证据的确定性 (证据质量) 纯文本摘要 住院 试验中的风险 优势比0.48 （95%置信区间 0.11 - 1.93） （随机对照） 19 每1000人 9 每1000人 中等 由于严重的 不精确性 3 住院治疗方面可能 几乎没有差异 差异：每1000人减少10例 (95%置信区间减少17例 — 增加17例) 住院 较高风险 优势比0.48 （95%置信区间 0.11 - 1.93） （随机对照） 33 每1000人 16 每1000人 低 由于非常严重的 不精确性4 瑞德西韦可能 比莫努匹拉韦更能 减少住院治疗 差异：每1000人减少17例 （95%置信区间减少29例 — 增加29例) 住院 最高风险 优势比0.48 （95%置信区间 0.11 - 1.93） （随机对照） 57 每1000人 28 每1000人 低 由于非常严重的 不精确性5 瑞德西韦可能 比莫努匹拉韦更能 减少住院治疗 差异：每1000人减少29例 (95%置信区间减少50例 — 增加47例) 导致停药的 不良反应 0 每1000人 9 每1000人 非常低 由于严重的偏倚 风险、不精确性和 间接性6 对导致停药的不良 事件的影响 尚不确定 差异：每1000人增加9例 (95%置信区间减少3例 — 增加21例) 症状消除时间 越低越好 （随机对照） 5.6 天（中位数） 7.9 天（均值） 非常低 由于极为严重的 不精确性7 对症状消除时间的 影响非常不确定 差异：平均差增加2.3 （95%置信区间减少1.9 — 增加7.8） 1. 间接性：严重。一些患者的死亡风险可能要高得多。这些患者的死亡率可能存在重要差异。不精确性：严重。事件很 少：瑞德西韦与对照组发生50个事件，莫努匹拉韦与对照组发生11个事件。 2. 偏倚风险：严重。莫努匹拉韦的证据存在高偏倚风险。间接性：严重。一些患者的机械通气风险可能要高得多。这些患 者在机械通气方面可能存在重要差异。 3. 不精确性：严重。可信区间包括重要益处和重要危害。 4. 不精确性：非常严重。可信区间包括重要益处和重要危害。 5. 不精确性：非常严重。可信区间包括重要益处和重要危害。 6. 偏倚风险：严重。间接性：严重。不精确性：严重。 7. 不精确性：极为严重。 6.5.1. 作用机制 瑞德西韦是为治疗丙型肝炎病毒感染而开发的，在转用于SARS-CoV-2之前，还在埃博拉病毒和马尔堡病毒感染中进行了研 究。瑞德西韦是一种核苷类药物。其作用机制涉及链终止，这与致死性诱变不同：在核糖核酸（RNA）基因组复制过程中，药物 由SARS-CoV-2聚合酶优先掺入内源性腺苷核苷中。与用于其他病毒的许多其他链终止核苷类药物不同，瑞德西韦引发链终止延 迟，因为核糖核酸合成在再添加三个核苷酸后终止，而不是在瑞德西韦掺入时终止(41)。 抗病毒药物耐药性的出现：在体外选择性压力下，SAR-CoV-2出现对瑞德西韦的耐药性，并与聚合酶序列编码中的突变 （E802D）相关(42)。E802D突变也在一项案例研究中报道，该研究描述了一名接受瑞德西韦的免疫功能低下患者在对药物发生短 暂病毒学反应后经历了高度病毒散发的复发(43)。尚不清楚这些观察对于瑞德西韦在门诊环境中广泛应用的临床意义。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 36 of 119 6.6. 莫努匹拉韦（2022年3月3日发布） 信息栏 关于莫努匹拉韦用于COVID-19非重症患者的建议已于2022年3月3日作为世卫组织动态指南的第九版发布，并在《英国医 学杂志》上作为快速建议发布。指南在关于药物疗法的LNMA提供了六项随机对照试验之后制定(1)。在本第十一版指南中，没 有对莫努匹拉韦的建议进行修订。 用于住院风险最高的COVID-19非重症患者（不包括孕妇和哺乳期妇女以及儿童） 有条件建议使用 我们建议使用莫努匹拉韦治疗（有条件建议使用）。 • 关于确定最高住院风险的患者的帮助，参见第6.1节。 • 有几种治疗方案可供选择：见决策支持工具，该工具展示了奈玛特韦-利托那韦、莫努匹拉韦、瑞德西韦和单克隆抗 体的利弊。 • 在缺乏临床证据的情况下，莫努匹拉韦对个体患者以及人群水平上的长期危害仍然未知。这些包括基因毒性，耐药性 和新变异株的出现（见“作用机制”）。 • 有条件的建议反映了在获得更多安全性数据之前，对使用莫努匹拉韦进行广泛治疗的关切。 • 使用莫努匹拉韦时应伴有缓解策略，例如避免在年轻成人中使用该药物、积极的药物警戒计划以及监测病毒聚合酶和 刺突序列（参见“理由”）。 实用信息 途径、剂量和疗程：三个实用问题摘要提供了其他考虑因素（莫努匹拉韦用于COVID-19，莫努匹拉韦用于COVID-19的给药, 接受莫努匹拉韦治疗COVID-19的患者的安全性和监测）。以下是关键要点的简明摘要： • 根据建议所参考的大型试验中评估的方案，莫努匹拉韦的建议剂量为800毫克片剂，每12小时一次，连续5天。 • 应在病程中尽早给药。在纳入的研究中，莫努匹拉韦在发病后5天内给药。 决策证据 利弊 在COVID-19非重症患者中，莫努匹拉韦很可能会减少入院时间和症状消退所需时间，并可能降低死亡率。莫努匹拉韦对机械 通气的影响十分不确定。治疗不会增加导致停药的严重不良事件的风险。 然而，在缺乏临床数据的情况下，莫努匹拉韦的潜在长期危害尚不确定，这仍然是一个令人关切的问题。潜在的危害包括产 生耐药性，以及莫努匹拉韦诱导突变风险的潜在危害。这些审议（见“理由”一节）基于莫努匹拉韦的作用机制和现有的临床前 数据（见“作用机制”一节）。 益处和潜在危害之间的平衡很接近，但如果与其他缓解策略一起实施以避免在个体和人群层面的危害（见“缓解策略”一 节），则倾向于支持将其用于最高风险组的治疗。单独使用莫努匹拉韦治疗（与单独使用其他抗病毒疗法一样）可能与产生耐药 性相关，正如使用其他抗病毒药物所见的情况（参见“作用机制”章节）。 莫努匹拉韦在防范住院治疗方面的绝对益处取决于预后。GDG定义了住院概率绝对减少6%的阈值，以代表大多数患者认为的 重要益处。莫努匹拉韦将在住院风险最高（高于基线风险10%）的患者中产生这样的益处，例如那些未接种COVID-19疫苗的患 者，老年人或患有免疫缺陷和/或慢性疾病的患者。在风险最高的人群中使用莫努匹拉韦的有条件建议体现了这一阈值：每1000名 患者减少60例住院治疗，且预期绝对生存益处更大，尽管这一点在没有数据的情况下无法量化。 由于缺乏公开报告或由调查人员提供的亚组数据，无法进行原计划的亚组分析。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 37 of 119 证据的确定性 证据摘要参考了六项试验，涉及被纳入LNMA（包括MOVe-OUT研究）的4796名参与者(44)。 证据的确定性评级为：在减少住院治疗方面，中等（因严重的不精确性而调低评级）；在死亡率方面，低（因严重的不精确 性和间接性而调低评级）；在症状消退所需时间方面，中等（因严重的偏倚风险而调低评级）；机械通气，很低（由于极其严重 的不精确性和严重的偏倚风险而调低评级）；以及，导致停药的严重不良反应，高。 现有基于实证开发的用以确定患者住院风险的风险预测工具存在局限性，这是导致GDG调低证据确定性等级的间接性原因的 主要来源(31)。此外，GDG认为，可能出现一些变异株（包括奥密克戎）导致当前可用的单克隆抗体的药效降低，因此也存在一 些间接性。 GDG决定，对于低事件发生率所反映的很低基线风险的结局（如死亡），不因不精确性而调低确定性评级。 价值观和偏好 根据商定的价值观和偏好（见第7节），GDG推断，几乎所有充分知情的、低住院风险的患者都会拒绝使用莫努匹拉韦，只有 风险最高的患者（如未接种疫苗、老年人或免疫抑制的患者）会选择这种治疗。 在缺乏研究证据的情况下，GDG在之前的一项调查中（参见卡西瑞单抗-伊德维单抗的建议）表达了这样一种观点，即大多数 住院风险超过10%因而绝对风险可降低6%的患者会选择接受治疗，而大多数低于该风险水平的患者会拒绝治疗。GDG为这项建议 完成了一项类似的调查。GDG表达了这样的观点：多数患者认为将绝对死亡风险降低每1000人3例（生存者从每1000名患者995人 增加到998人）是很重要的。 资源和其他考虑因素 可接受性和可行性 并非所有愿意选择接受此疗法的人都能获得莫努匹拉韦。这强化了莫努匹拉韦应保留给最高风险人群的观点。 令人关切的是，由于成本和可得性的原因，低收入和中等收入国家（LMICs）面临获取此项治疗的障碍(38)。在低收入和中等 收入国家中，就莫努匹拉韦进行共同决策、并就其危害与益处开展沟通方面的挑战也可能增加。例如，在出现症状的最初5天，社 会经济的弱势群体往往较少能获得服务（包括诊断测试和治疗），因而少有机会获取干预措施。因此，如果由风险最高的患者接 受干预，可能会加剧卫生不公平。重要的是，各国应将COVID-19临床护理路径纳入卫生系统中可为COVID-19非重症患者提供护 理的部分（即初级保健、社区护理环境）。 这些建议应激励调动所有可能的机制参与改善此干预措施的全球可及性。例如，2021年12月17日，世卫组织发布了第7次邀 请，请COVID-19疗法制造商向世卫组织预认证部门提交产品评估意向书（EOI），其中包括莫努匹拉韦。如果该评估表明某一产 品及其相应的生产（和临床）地点符合世卫组织建议的标准，则该产品将被列入联合国组织和其他机构认为可采购的医药产品清 单。各国可根据可用资源制定自己的指南，并相应地确定治疗方案的优先次序。 获得SARS-CoV-2诊断：由于该建议强调需要在出现症状后5天内给与莫努匹拉韦治疗；增加诊断测试的可及性并确保其正确 使用至关重要。因此，需要提供并使用可靠且及时的COVID-19诊断测试（包括使用核酸扩增检测（NAAT)和抗原快速诊断检测 （Ag-RDT））来改善药物的可及性，特别是那些针对疾病早期阶段的药物。个人和训练有素的专业人员适当使用抗原快速诊断检 测可以改善早期诊断和早期获得临床护理的机会，特别是在社区和初级卫生保健环境中。国家规划应优化其检测系统，以反映当 地流行病学、应对目标、可用资源和人群需求。 理由 结合证据、基于临床前数据的安全关切、价值观和偏好以及可行性，提出了仅在住院风险最高的COVID-19非重症患者中使用 莫努匹拉韦的有条件建议。最高风险人群的典型特征包括未接种疫苗者、老年人或存在免疫缺陷和/或慢性疾病（例如糖尿病）的 患者。 只有少数风险最高的患者可能获得足够的益处来补偿治疗的风险以及其他局限性和缺点。这些包括缺乏识别高风险患者的可 靠工具，药物的可得性有限以及下列总结的安全关切。 • GDG担心因使用新的抗病毒药物作为单一疗法而产生耐药性的风险（见“作用机制”部分）。关于耐药性多快出现存在 很大的不确定性；因缺乏足够临床数据，GDG的结论是仍存在很大的不确定性。 • 关于药物促进新变异株出现的风险，GDG指出，该药物导致选择压力而产生新变异株的可能性很低；因缺乏足够的临床 数据，仍存在很大的不确定性。 • 莫努匹拉韦在体外哺乳动物细胞中具有致突变性，但在动物模型或人类中没有致突变性的证据。因此，GDG承认，与莫 努匹拉韦相关的长期遗传毒性和恶性肿瘤的可能性存在不确定性。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 38 of 119 • 鉴于大鼠幼崽对生长板厚度有影响的证据，莫努匹拉韦不应用于儿童。同样，由于在对妊娠动物给药时，莫努匹拉韦在 动物后代中引起胚胎-胎儿致死性和致畸性，因此不应将其用于孕妇或哺乳期妇女。 • GDG承认，精子形成也可能特别容易受到莫努匹拉韦的致突变作用，但正在或近期接受莫努匹拉韦治疗的父亲所生育儿 童的后果存在不确定性。 适用性 目前尚不确定本建议对儿童、哺乳期妇女和孕妇的适用性，因为所纳入的随机对照试验所招募的都是未怀孕的成年人。然 而，GDG的结论是不应向患有COVID-19的儿童、哺乳期妇女或孕妇提供莫努匹拉韦。此外，应向有生育计划的男性告知治疗对精 子形成可能的遗传毒性作用（参见缓解策略部分）。与老年患者相比，年轻患者中未知的长期遗传毒性风险可能更高，因此应避 免将其用于非高风险的年轻人。 GDG还担心，对奥密克戎等新出现的需要关注的变异株，该药物是否仍能保持效力。尽管认为丧失效力缺乏分子学依据，但 GDG指出，较高的病毒载量和与之相关的疾病严重程度可能影响莫努匹拉韦的有效性。这代表了另一个不确定的领域，因为目前 可用的数据不包括感染较新变异株（包括奥密克戎）的患者（见第9节)。 临床问题/PICO 对象：COVID-19非重症患者 干预：莫努匹拉韦 对照：标准治疗 摘要 证据摘要 莫努匹拉韦的LNMA参考了六项随机对照试验，在门诊环境中招募了4827名非重症患者；LNMA团队获得了4796名患者的 数据。所有随机对照试验均已登记，没有一项发表在同行评审的期刊上。纳入的研究中没有一项招募了儿童或孕妇。附录总结 了莫努匹拉韦对比标准治疗的研究特征和偏倚风险评级、按结局划分的效果估计，以及莫努匹拉韦对比标准治疗的相关森林 图。 针对COVID-19非重症患者，建议分级的评估、制定和评价(GRADE)的结论摘要表显示了对于人们关注的结局，莫努匹拉 韦与标准治疗对比的相对和绝对效果，附有证据确定性评级，由LNMA提供信息(3)。 亚组分析 GDG要求进行五项预设的亚组分析： 1. 年龄：儿童（19岁及以下）、成人（20-60岁）、老年人（60岁及以上）。 2. 治疗开始时的疾病严重程度：非重症、重症、危重症。 3. 出现症状的时间。 4. 血清学状态（血清阳性、血清阴性）。 5. 疫苗接种状态（未接种疫苗、已接种疫苗）。 研究没有纳入儿童，也没有纳入重症或危重症患者。所有研究均招募了出现症状不足5天的未接种疫苗的个体。未报告血 清学状态数据。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 莫努匹拉韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.06 （95%置信区间 0-0.4） 基于6项研究中4796名 参与者的数据。 （随机对照） 6 每1000人 0 每1000人 低 因严重的不精确性 和间接性 1 莫努匹拉韦 对死亡率可能 有很小的效果 差异：每1000人减少6例 （95%置信区间减少6例 — 减少4例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 39 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 莫努匹拉韦 证据的确定性 （证据质量） 纯文本摘要 机械通气 优势比1 （95%置信区间0.02-59.74） 基于1项研究中1220名 参与者的数据。 （随机对照） 8 每1000人 8 每1000人 非常低 因严重的偏倚风险 和极为严重的 不精确性 2 莫努匹拉韦对机械 通气的影响十分 不确定 差异：每1000人减少0例 （95%置信区间减少8例 — 增加317例） 住院 试验中的风险 优势比0.54 （95%置信区间0.3-0.89） 基于5项研究中4688名 参与者的数据。 （随机对照） 35 每1000人 19 每1000人 中等 因严重的不精确性 3 莫努匹拉韦 很可能减少住院 差异：每 1000 人减少 16 例 （95%置信区间减少 24例 — 减少 4例） 住院 风险较高 优势比0.54 （95%置信区间0.3- 0.89） 基于5项研究中4688名 参与者的数据。 （随机对照） 60 每1000人 33 每1000人 中等 因严重的不精确性 4 莫努匹拉韦 很可能减少住院 差异：每 1000 人少 27 例 （95%置信区间减少 41例 — 减少 6例） 住院 风险最高 优势比0.54 （95%置信区间 0.3-0.89） 基于5项研究中4688名 参与者的数据。 （随机对照） 100 每1000人 57 每1000人 中等 因严重的不精确性 5 莫努匹拉韦 很可能减少住院 差异：每 1000 人减少 43 例 （95%置信区间减少 68例 — 减少 10例） 导致停药的 不良反应 基于6项研究中4796名 患者的数据（随机对照） 0 每1000人 0 每1000人 高 在导致停药的 不良反应方面几乎 没有差异 差异：每 1000 人减少 0 例 （95%置信区间减少 0例 — 增加 2例） 症状消除 所需时间 越低越好 基于 3项研究中 3078名 患者的数据（随机对照） 9 天（中位数） 5.6 天（均值） 中等 由于严重的 偏倚风险 6 莫努匹韦很可能 减少症状持续时间 差异：平均差减少3.4 （95%置信区间减少4.8 — 减少1.7） 恶性肿瘤 体外和动物研究提示致癌的可能性 非常低 无长期随访的 人类数据 莫努匹拉韦对 癌症的影响 十分不确定 1. 间接性：严重。整个人群的基线风险很低，这意味着对死亡率的任何影响都将非常小。有些人的基线风险要高得多，这 些人不容易识别。对于这些患者，莫努匹拉韦可能对死亡率有重要影响。不精确性：严重。总共只有11个事件（对照组 10个，莫努匹拉韦组1个）。 2. 偏倚风险：严重。报告机械通气的唯一试验不是盲法试验。不精确性：极为严重。事件数量很少，导致包含重要和不重 要影响的可信间隔很大。 3. 不精确性：严重。可信区间上限包括对住院治疗的小而不重要的影响（每1000人减少4例）。 4. 不精确性：严重。可信区间上限包括对住院治疗的小而不重要的影响（每1000人减少4例）。 5. 不精确性：严重。可信区间上限包括对住院治疗的小而不重要的影响（每1000人减少4例）。 6. 偏倚风险：严重。所有三项试验偏离预期干预的偏倚风险高（缺乏盲法）。一项试验因随机化隐匿可能不足而存在高偏 倚风险。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 40 of 119 解决安全关切的缓解策略 信息栏 鉴于与莫努匹拉韦相关的安全关切（见“作用机制”部分），世卫组织认识到需要减轻个体患者和人群水平的风险。 有条件的建议考虑了这样一种策略：将干预限制在住院或死亡风险较高的患者身上。较高风险人群的典型特征包括年龄较 大、患有免疫缺陷和/或慢性疾病（例如糖尿病）和未接种COVID-19疫苗者。更多详情参见世卫组织免疫接种战略咨询专家组 COVID-19疫苗接种建议。 其他缓解策略包括： • 关于使用莫努匹拉韦治疗的决定必须使用共享决策模型，确保临床医生对疗法的潜在益处和危害有良好的了解，并能 够向患者解释这些益处和危害以便其做出充分知情的决策。参阅实用信息部分。 • 莫努匹拉韦不应用于孕妇或哺乳期妇女或儿童。如果对怀孕存疑，应在开始治疗前进行验孕。如果考虑对育龄 妇女进行治疗，应协助其在治疗期间以及最后一剂莫努匹拉韦后4天内进行节育咨询。 • 对于有生育计划的男性，应告知其治疗对精子形成可能的暂时遗传毒性，并应建议那些与女性保持性活跃的男 性，在治疗期间以及最后一剂莫努匹拉韦后至少3个月内采取节育措施(46)。 • 与老年患者相比，年轻患者中遗传毒性的长期风险可能更高。因此应限制该药用于非高危人群的年轻人。 • 针对临床呼吸道样本中检测到的SARS-CoV-2（即可能包括聚合酶和刺突），应为接受治疗的患者（包括较高风险个 体（免疫受损者））安排主动序列监测。 • 药物警戒：使用莫努匹拉韦时应伴有强有力的、积极的药物警戒计划。 6.6.1. 作用机制 莫努匹拉韦是一种口服抗病毒药物，最初作为流感治疗药物开发，但尚未获批准。该药物抑制SARS-CoV-2的复制，广泛的体 外效力与瑞德西韦相似，并在开发的早期被改用作SARS-CoV-2的抗病毒药物(47)(48)。 莫努匹拉韦是ß-D-N4-羟基胞苷（下称NHC）的口服前体药物。它是一种核苷类药物，但作用机制涉及病毒的致命突变。这与 其他抗病毒核苷类似药物（例如瑞德西韦以及用于艾滋病毒或丙肝病毒的药物）的链终止机制不同(49)。在复制核糖核酸（下称 RNA）模板基因组期间，羟基胞苷由SARS-CoV-2依赖RNA的RNA聚合酶（RdRp）（而不是C或U核苷）纳入基因组或亚基因组 RNA中。然后，由此产生的含有羟基胞苷的RNA本身被用作生成后续RNA的模板。预测这些后续RNA会突变，因而被认为不会形 成功能性病毒(49)(50)。 莫努匹拉韦每日两次口服，而瑞德西韦则是每日一次通过静脉输注。在健康志愿者中，莫努匹拉韦（800mg）达到的活性代 谢物的最大血浆浓度为3600纳克/毫升(51)。这高于瑞德西韦（2200纳克/毫升）(52)。然而，与瑞德西韦活性代谢物相比（35小 时），莫努匹拉韦活性代谢物在人细胞系中的细胞内半衰期更短（3小时）(51)。 高剂量的莫努匹拉韦（250毫克/公斤，每日两次）已被证明对感染SARS-CoV-2的叙利亚金黄地鼠有效；然而，没有关于动物 与人类血浆药代动力学的比较报告(53)。抗病毒活性的证据也来自一项对感染SARS-CoV-2的雪貂的较低剂量研究(54)。当莫努匹 拉韦与法匹拉韦联合治疗受感染的叙利亚金黄地鼠时，疗效大于单独给予任何一种药物(55)。 莫努匹拉韦保持对阿尔法和贝塔变异株的体内活性(56)，以及对德尔塔和奥密克戎变异株的体外活性(57)(58)。目前没有数据 证明其对德尔塔或奥密克戎变异株的体内活性，虽然似乎没有支持活性丧失的分子学基础，但围绕更快的复制或传播速度是否可 能影响药效仍存在不确定性。 耐药性的出现：用于其他病毒的药物的耐药性出现是各不相同的；有些很容易出现，有些则出现得较慢。通常认为，对于给 定药物和给定病毒，产生耐药性所需的突变数量越多，耐药性屏障越高。目前没有足够的数据以确定莫努匹拉韦对SARS-CoV-2的 耐药性屏障有多高。根据使用其他核苷类抗病毒药物的经验（有些耐药性屏障高，有些耐药性屏障低），莫努匹拉韦将在个体体 内产生病毒耐药突变的选择压力，并有可能在人群水平上传播。因此需要非临床和/或临床数据，但目前关于莫努匹拉韦没有这些 数据。 耐药性因病毒序列的固有多样性而出现，在病毒复制时自发发生。在药物的存在下，当偶然变异具有生存优势时，它们就会 被选择，称为选择压力。有时病毒付出了健康成本，随后可以选择继发突变来恢复健康。主要的不确定性在于耐药性出现的速 度，而并非是否会出现。对于免疫功能受损的患者，耐药性风险可能更高，因为该群体的复制更加长尾。在依从性差的患者中， 病毒暴露于次优的药物浓度，也可能存在更高的耐药风险。联合使用药物会减慢耐药性出现的速度，因为与使用一种药物相比， 需要更多的突变来赋予对多种药物以耐药性。值得注意的是，动物研究也表明联合用药更有效。耐药性给个体患者造成的风险是 因疗效降低而导致的药物失效。如果耐药性被传播，则在人群水平上存在失去疗效的风险，并且后续与伴侣药物联合用药的尝试 可能因“功能性的单一疗法”而徒劳无功。由于缺乏数据，无法估计耐药性的遗传屏障。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 41 of 119 新变异株的出现：有人提出，由莫努匹拉韦的作用机制所致的随机诱变可能会增加病毒序列的多样性，这可能导致新变异株 的更快出现(59)。与耐药性的考虑不同，缺乏概念基础支持莫努匹拉韦造成新变异株的出现的选择压力。鉴于莫努匹拉韦仅替代基 因组中四个核苷酸碱基中的两个，而不是替代基因组中的所有核苷酸，其序列变异性相对较低。没有直接证据支持或反驳变异株 假设，因此风险目前无法量化。 已承认的是，接受干预的患者数量越多，耐药性出现的速度越快，且导致新变异株产生的病毒基因组多样性风险越高。 非临床安全性：GDG审查了美国食品和药物管理局用于授权紧急使用莫努匹拉韦的会议文件中关于莫努匹拉韦非临床安全性 的公开数据（2021年11月30日）(60)。其中强调了以下安全关切： • 遗传毒理学数据表明，莫努匹拉韦在体外具有致突变性，但在动物模型中没有致突变的证据。GDG承认现有数据中存在 不确定性并得出结论：根据现有信息，莫努匹拉韦对人类可能致癌，也可能不致癌。 • 在快速生长的大鼠中观察到与骨形成减少相关的生长板厚度的增加，但在小鼠、大鼠或狗中则没有观察到此种情况。 GDG因此决定不应将莫努匹拉韦用于儿童患者。 • 重要的是，在大鼠的10天幼崽中可检测到低浓度的NHC（0.09%母体暴露），这表明NHC存在于母乳中。GDG决定不应 将莫努匹拉韦用于儿童患者。 • 在发育和生殖毒理学评估中，观察到大鼠和兔子的胎儿体重减轻，较高的暴露也与大鼠的胚胎 - 胎儿致死性和致畸性有 关。因此，莫努匹拉韦不应在妊娠期间给药。 • 缺乏与精子形成相关的可用数据，成年男性的精子形成可能特别容易受到突变原的影响。对正在或近期接受莫努匹拉韦 治疗的父亲，缺乏数据以量化药物对其孕育的胚胎/胎儿的影响。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 42 of 119 6.7. Janus激酶抑制剂（2022年1月14日发布） 信息栏 2022年1月14日，关于对COVID-19重症和危重症患者使用janus激酶（下称JAK）抑制剂（具体为巴瑞替尼、鲁索替尼和托 法替尼）进行治疗的建议作为世卫组织动态指南第八版发布，并在《英国医学杂志》上作为快速建议发表。在该建议之前，药 物治疗的LNMA提供了3项巴瑞替尼随机对照试验、2项鲁索替尼随机对照试验和1项托法替尼随机对照试验的数据(1)。在本第 十一版指南中，没有修订JAK抑制剂的建议；但是，我们知晓支持我们先前建议的“康复”试验已于最近发表，并且正在进行 审查。 巴瑞替尼，用于COVID-19重症或危重症患者 强烈建议使用 新增 我们建议使用巴瑞替尼治疗（强烈建议使用）。 • 皮质类固醇也应与巴瑞替尼一起用于COVID-19重症或危重症患者（见第6.15节）。 • 之前已建议白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）用于治疗COVID-19重症或危重症患者（见第6.11节）。白 介素-6受体阻滞剂和巴瑞替尼不应同时使用，应视为替代药物。选择使用巴瑞替尼还是白介素-6受体阻滞剂取决于可 获得性，以及临床和背景因素（见“理由”）。 实用信息 实用问题摘要中列举了其他考虑因素。在美国食品和药物管理局（FDA）基于巴瑞替尼的紧急使用授权（EUA）面向医疗保 健提供者的情况说明书中也可获得有用的信息(61)。以下是关键要点的简明摘要： 途径、剂量和疗程： • 对于成人（估算肾小球滤过率≥60毫升/分钟/1.73平方米）建议剂量为每日4毫克，口服。 • 总共持续治疗14天或直至出院，以先到者为准。尚不清楚最佳治疗时长，建议的疗程反映了提供关于巴瑞替尼疗效证据 的试验所用的治疗时间。 剂量方案调整： • 白细胞减少症，肾功能损害或肝损伤的患者（注意：在治疗期间应监测这些参数）； • 服用强有机阴离子转运蛋白3（OAT3）抑制剂（例如丙磺舒）的患者，因药物相互作用需减少剂量。 用药时机：与白介素-6受体阻滞剂相同，巴瑞替尼应与全身性皮质类固醇一起开始使用；没有明确在住院期间或病程中的具 体使用时间。 决策证据 利弊 在重症或危重症患者中，巴瑞替尼很可能会降低死亡率以及机械通气时长，并缩短住院时间。它很可能几乎不会导致严重不 良事件的增加。 将JAK抑制剂作为一类（而不是单个药物）进行了亚组分析，没有证据显示对较年轻（不足70岁）对比老年患者；COVID-19 危重症对比重症患者；接受对比未接受皮质类固醇基线治疗者；以及接受对比未接受瑞德西韦基线治疗者之间的相对风险存在亚 组效应。 证据的确定性 证据的确定性被评为：降低死亡率方面：中等（调低评级的原因是：对于一项大型正在进行的试验，由于接近28天的随访期 相对较短，该试验可能不足以捕获所有可能改变效果和间接性估计的相关事件）；减少住院时间方面：高；在减少机械通气时长 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 43 of 119 以及很少或未增加严重不良事件方面：中等（两者都因严重的不精确性而调低评级）；以及在机械通气需求方面：低，由于非常 严重的不精确性而调低评级。 GDG特别指出，根据感染（如结核病）的背景流行率，世界不同地区严重感染（细菌和真菌）的风险可能有很大差异。鉴于 巴瑞替尼用于治疗COVID-19的疗程较短，这可能并不那么重要，但由于纳入试验的地理分布有限且随访期短，证据是有限的。 价值观和偏好 应用商定的价值观和偏好（见第7节），GDG推断，几乎所有充分知情的COVID-19重症或危重症患者都希望接受巴瑞替尼， 因其可能降低死亡率，且有中等确定性证据表明其很少或未增加严重不良事件。巴瑞替尼对死亡率的益处被认为对患者至关重 要，而关于其很少或未增加严重不良事件的中等确定性证据使GDG更加放心。GDG预计不同患者对这一干预措施的价值观和偏好 鲜有差异。 资源和其他考虑因素 对资源的影响、公平和人权 与COVID-19的一些其他候选治疗相比，巴瑞替尼价格昂贵。该建议未考虑成本效益。在世界许多地方都难以获得此类药物， 而且如果没有协调一致的努力，这种情况可能会持续下去，特别是在资源匮乏的地区。因此，此项强烈建议可能会加剧卫生不公 平。另一方面，鉴于对患者的已证实益处，此项建议也应能激励人们采用所有可能的机制以提高此类疗法在全球的可获得性。各 个国家可根据可用资源制定自己的指南并相应地确定治疗方案的优先次序。2021年12月17日，世卫组织发布了第7次邀请，请 COVID-19疗法制造商向世卫组织预认证部门提交产品评估意向书(EOI)，其中包括巴瑞替尼。 当药物短缺时，可能有必要通过临床分诊(6)确定使用巴瑞替尼的优先次序，例如优先基线死亡风险最高的患者（如危重症患 者优先于重症患者）使用，因为他们获得的治疗的绝对益处最大。其他优先排序建议（缺乏直接证据）包括，重点优先临床病程 持续恶化的患者，以及避免对已确诊多器官衰竭的患者使用巴瑞替尼治疗（这些患者的获益可能较小）。 可接受性和可行性 由于巴瑞替尼每天口服一次，住院患者应该很容易接受这种治疗。对于不能吞咽片剂的患者，可将巴瑞替尼压碎、溶于水 中，并通过鼻饲管给予（参见实用信息）。 理由 当从证据出发强烈建议在COVID-19重症或危重症患者中使用巴瑞替尼时，GDG强调了生存、缩短住院时间，易于给药、并且 可能几乎没有可归因于该药物的严重不良事件等益处。GDG承认，因纳入的试验相对较短的随访期，可能未准确捕获某些严重的 不良事件（如真菌感染）。 由于作用机制不同，GDG将巴瑞替尼与其他（下述）JAK抑制剂分开考虑。 成本和药物的可及性是重要的考虑因素，同时GDG也认识到这项建议可能会加剧卫生不公平。这一强烈建议将会推动解决这 些问题，并促进各个区域和国家的最大可及性。GDG预期患者的价值观和偏好没有重要差异，并判断其他背景因素不会改变本建 议（见“决策证据”）。 新出现的证据 当做出使用巴瑞替尼治疗的强烈建议时，GDG仔细考虑了一项当时尚未发表的大型试验（“康复”）的影响（该试验将患者 随机分配到巴瑞替尼组或无巴瑞替尼组）。关于该试验的不确定性包括同时接受白介素-6受体阻滞剂的患者所占比例（见下文） 以及何时可获得该信息。GDG认为，受到中等至高度确定性证据的支持，巴瑞替尼的益处充分，可立即强烈建议使用该药物，并 准备在“康复”试验数据公布后视需要更新动态指南。该“康复”试验现已发表（参考文献），并证实了巴瑞西替尼对COVID-19 重症和危重症患者的有益作用。一旦LNMA得到更新，GDG将在下一次更新指南之前，充分评估巴里西替尼的更新证据。 白介素-6受体阻滞剂与巴瑞替尼的相互关系 GDG先前曾强烈建议对COVID-19重症或危重症患者使用白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）。GDG基于目前的证 据仔细考虑了巴瑞替尼应作为白介素-6受体阻滞剂的替代药物还是作为其补充药物。二者的联合使用可能会不可接受地增加危 害，包括继发性细菌和真菌感染。在缺乏增量益处证据的情况下，GDG建议临床医生不要同时给药。 随之出现的问题是，基于何种依据在白介素-6受体阻滞剂和巴瑞替尼之间进行选择（见研究证据）。这些药物未经直接比 较，因此其相对效果的最佳证据来自为这些指南提供信息的LNMA所进行的间接比较。与白介素-6 受体阻滞剂相比，巴瑞替尼可 降低死亡率（低确定性），并可能缩短机械通气的时长（低确定性）。药物对机械通气的影响可能很小或没有差异（低确定 性），且导致停药的不良事件可能几乎没有差异（中等确定性）（参见研究证据中的研究结果摘要表）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 44 of 119 GDG认为，低确定性证据不足以基于它们对患者重要的益处和危害的影响做出巴瑞替尼优于白介素-6受体阻滞剂的建议。因 此，当两种药物都可用时，临床医生应根据其他考虑因素在二者之间进行选择。这些因素可能包括使用药物的体验和舒适度；地 方机构政策；给药途径（巴瑞替尼是口服的；白介素-6受体阻滞剂是静脉注射的）；以及成本。 适用性 所纳入的随机对照试验都没有招募儿童，因此本建议对儿童的适用性尚不确定。在向孕妇或哺乳期妇女施用巴瑞替尼方面也 存在不确定性。孕妇患者应与其卫生服务提供者讨论此疗法潜在的益处是否值得其对母亲和胎儿的潜在风险（见研究证据和实用 信息标签），从而决定是否使用此疗法。 临床问题/PICO 对象：巴瑞替尼用于COVID-19重症或危重症患者 干预：巴瑞替尼 对照：标准治疗 摘要 证据摘要 巴瑞替尼的LNMA由三项随机对照试验支持，这些随机对照试验招募了2659名不同疾病严重程度的患者(62)(63)(64)。所有 随机对照试验均已登记，其中两项发表在同行评议的期刊上(63)(64)；一项研究是预印本(62)。所有三项随机对照试验均在住院 环境中招募患者。没有一项纳入的研究招募了儿童或孕妇。此表显示了随机对照试验的特征。 对于COVID-19重症或危重症重症患者，建议分级的评估、制定和评价(GRADE)的结论摘要表显示，对于人们关注的结 局，巴瑞替尼与常规治疗对比的相对效果和绝对效果，以及证据确定性评级，由LNMA提供信息(1)。 基线风险估计值 对于重症和危重症，就死亡率这一关键结局应用的基线风险估计值为13%（130/1000）。对于本指南中的其他相关建议， 其估计值来自针对重症和危重症患者的“团结”试验，并根据皮质类固醇的治疗效果进行了调整。对于其他结局，我们使用了 提供证据的随机对照试验中对照组的中位数（见第7节）。 亚组分析 将JAK抑制剂作为一类而不是单个药物，针对其进行了四项预设的亚组分析： 1. 年龄：较年轻成年人（不足70岁）对比老年人（70岁及以上）。 2. 治疗开始时的疾病严重程度：非重症、重症、危重症。 3. 同时使用皮质类固醇。 4. 与基线瑞德西韦联合用药。 对于所有预设的效应修正因子，没有证据显示在关键结局的相对风险方面存在亚组效应。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 巴瑞替尼 证据的确定性 （证据质量) 纯文本摘要 死亡率 优势比0.62 （95%置信区间 0.44 - 0.85） 基于3项研究中2659名 参与者的数据。 （随机对照） 130 每1000人 85 每1000人 中等 因在大型随机对照 试验中持续招募 巴瑞替尼很可能 降低死亡率 差异：每1000人减少45例 （95%置信区间减少68例-减少17例） 机械通气 优势比0.8 （95%置信区间 0.52 - 1.19） 基于2项研究中2434名 参与者的数据 （随机对照） 116 每1000人 95 每1000人 低 因严重的不精确性1 巴瑞替尼可能 会减少机械通气 差异：每1000人减少21例 （95%置信区间减少52例 — 增加19例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 45 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 巴瑞替尼 证据的确定性 （证据质量) 纯文本摘要 导致停药的 不良反应 基于2项研究中1611名 患者的数据 （随机对照） 0 每1000人 5 每1000人 中等 因严重的不精确性2 巴瑞替尼很可能 几乎不会导致严重 不良事件的增加 差异：每1000人减少5例 （95%置信区间增加0例 — 增加28例） 住院时长 越低越好 基于3项研究中2652名 参与者的数据。 （随机对照） 12.8 天（中位数） 11.4 天（均值） 高 巴瑞替尼缩短 住院时间 差异：平均差减少1.4天 （95%置信区间减少2.4天 — 减少0.4天） 机械通气 持续时间 越低越好 基于2项研究中328名 参与者的数据。 （随机对照） 14.7 天（中位数） 11.5 天（均值） 中等 因严重的不精确性3 巴瑞替尼很可能会 减少机械通气的时长 差异：平均差减少3.2天 （95%置信区间减少5.9天 — 减少0.5天） 临床稳定 所需时间 越低越好 基于2项研究中2558名 参与者的数据。 （随机对照） 9.9 天（中位数） 8.9 天（均值） 低 因严重的不精确性4 巴瑞替尼可缩短临床 稳定所需时间 差异：平均差减少1天 （95%置信区间减少2.9天 — 增加1.1天） 1. 不精确性：非常严重。可信区间包括机械通气的重要减少和增加。 2. 不精确性：严重。可信区间包括不良反应的重要增加。 3. 不精确性：严重。可信区间内无重要差异。 4. 不精确性：非常严重。可信区间包括重要伤害和重要益处（使用 1 天作为最小重要差异阈值）。 临床问题/PICO 对象：巴瑞替尼用于COVID-19重症和危重症患者 干预：巴瑞替尼 对照：白介素-6受体阻滞剂 结局 时限 研究结果和衡量标准 对照 白介素-6受体阻滞剂 干预 巴瑞替尼 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.77 （95%置信区间 0.53-1.1） 基于3项研究中2659名 参与者的数据。 （随机对照） 118 每1000人 96 每1000人 低 因在大型随机对照 试验中的严重的 不精确性和 持续招募1 巴瑞替尼可能 降低死亡率。 差异：每1000人减少22例 （95%置信区间减少52例 — 增加9例） 机械通气 优势比1.01 （95%置信区间 0.61-1.6） 基于2项研究中2434名 参与者的数据。 （随机对照） 94 每1000人 96 每1000人 低 因严重的不精确性2 机械通气方面可能 几乎没有差异。 差异：每1000人增加2例 （95%置信区间减少38例 — 增加44例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 46 of 119 结局 时限 研究结果和衡量标准 对照 白介素-6受体阻滞剂 干预 巴瑞替尼 证据的确定性 （证据质量） 纯文本摘要 导致停药的 不良反应 基于4项研究中2309名 参与者的数据。 （随机对照） 0 每1000人 1 每1000人 中等 因严重的不精确性3 在导致停药的严重 不良事件方面， 很可能几乎 没有差异。 差异：每1000人增加1例 （95%置信区间减少11例-增加15例） 住院时长 越低越好 基于3项研究中2652名 参与者的数据。 （随机对照） 8.1 天（中位数） 11.2 天（均值） 很低 因严重的偏倚 风险、严重的 不一致性和严重的 不精确性4 对住院时长的影响 十分不确定。 差异：平均差增加3.1天 （95%置信区间减少3.8天-增加9.9天） 机械通气时长 越低越好 基于2项研究中328名 参与者的数据 （随机对照） 13.8 天（中位数） 11.6 天（均值） 低 因严重的偏倚风险 和不精确性5 巴瑞替尼可能减少 机械通气的时长。 差异：平均差减少2.2天 （95%置信区间减少5.3例 — 减少0.7例） 临床稳定 所需时间 越低越好 基于2项研究中2558名 参与者的数据 （随机对照） 8.4 天（中位数） 8.9 天（均值） 低 因严重的偏倚风险 和不精确性6 对临床稳定所需 时间可能没有 重要影响。 差异：平均差增加0.5天 （95%置信区间减少2.3例 — 增加3.2例） 1. 不精确性：严重。可信区间内无重要差异。 2. 偏倚风险：无严重风险。关于白细胞介素-6受体阻滞剂的大部分数据来自非盲法试验。不精确性：非常严重。可信区间 包括重要利益和重要危害。 3. 不精确性：严重。可信区间包括重要小但重要的危害。 4. 偏倚风险：严重。关于白细胞介素-6受体阻滞剂的大部分数据来自非盲法试验。不一致性：严重。研究白介素-6受体阻滞 剂的试验结果不一致：有些增加了住院时长，有些则缩短了住院时长。不精确性：非常严重。可信区间包括重要利益和重要 危害。 5. 偏倚风险：严重。关于白细胞介素-6受体阻滞剂的大部分数据来自非盲法试验。不精确性：严重。可信区间内无重要差 异。 6. 偏倚风险：严重。关于白细胞介素-6受体阻滞剂的大部分数据来自非盲法试验。不精确性：严重。可信区间包括重要危 害和重要益处（使用1天作为最小重要差异阈值）。 鲁索替尼和托法替尼，用于COVID-19重症或危重症患者 有条件建议不使用 我们建议不使用鲁索替尼或托法替尼（有条件建议不使用）。 • 仅当巴瑞替尼和白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）均不可用时，临床医生才应考虑使用这些药物。 • GDG强调需要更多的试验证据，以更好地为建议提供信息。 实用信息 途径，剂量和疗程：在没有其他可用信息的情况下，我们参考试验特征表（鲁索替尼和托法替尼）来指导这些药物的给药。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 47 of 119 用药时机：与白介素-6受体阻滞剂相同，鲁索替尼或托法替尼应与全身性皮质类固醇同时开始使用；没有明确在住院期间或 病程中的具体使用时间。 决策证据 利弊 鲁索替尼或托法替尼对死亡率、机械通气需求和住院时长的影响仍不确定。托法替尼可能增加导致停药的不良事件。 将JAK抑制剂作为一类（而不是单个药物）进行了亚组分析，没有证据表明其对以下相对风险存在亚组影响：较年轻（不足70 岁）对比老年患者；接受对比未接受皮质类固醇治疗者；COVID-19重症对比危重症患者；以及接受对比未接受瑞德西韦治疗者。 证据的确定性 由于小群组引起的严重的不精确性（鲁索替尼：两项随机对照试验，475名患者；托法替尼：一项随机对照试验，289名患 者），事件少且间接性严重（与鲁索替尼的随机对照试验有关，大多数患者未接受皮质类固醇），对于两种药物的所有重点结 局，证据确定性被评为低或很低。 价值观和偏好 应用商定的价值观和偏好（见第7节），GDG推断，鉴于在死亡率和其他优先获益结局方面的证据确定性低或很低，以及严重 不良反应的可能性仍存在，大多数充分知情的患者不希望接受鲁索替尼或托法替尼。然而，GDG预计，由于尚未排除益处，并且 由于可能存在JAK抑制剂的类效应（例如，巴瑞替尼为其他JAK抑制剂提供了间接的益处证据），在巴瑞替尼和白介素-6受体阻滞 剂（托珠单抗或萨利鲁单抗）均不可用的情况下，少数充分知情的患者会选择接受其中一种或另一种药物。 资源和其他考虑因素 对资源的影响、公平和人权 GDG指出，鉴于反对使用鲁索替尼或托法替尼的建议，确保药物可及性的努力应聚焦于目前建议的药物。 可接受性和可行性 由于鲁索替尼和托法替尼采取口服、每日两次，因此对于COVID-19重症和危重症住院患者，这种治疗应易于接受。对于无法 吞咽整片的患者中，可以将药片溶于水中口服或通过鼻饲管给药（实用信息）。 理由 在基于证据有条件建议在COVID-19重症或危重症患者中不使用鲁索替尼或托法替尼时，GDG强调了在死亡率、机械通气时长 以及可能增加严重不良事件（尤其是对于托法替尼）方面，证据的确定性低或很低。 GDG强调需要更多的试验证据，以更好地为建议提供信息；预期通过持续进行针对这些JAK抑制剂的试验获得证据。 适用性 纳入的随机对照试验均未招募儿童；鉴于此，此项建议对儿童的适用性尚不确定。在向孕妇或哺乳期妇女施用鲁索替尼或托 法替尼方面也存在不确定性。 临床问题/PICO 对象：COVID-19重症或危重症患者 干预：鲁索替尼 对照：标准治疗 摘要 证据摘要 对鲁索替尼进行的LNMA参考了2个随机对照试验，共招募了475名非重症、重症和危重症亚组的患者(65)(66)。两项随机对 照试验均已登记，一项发表在同行评审期刊上，一项仅是试验登记。两项随机对照试验均招募了住院患者。没有一项纳入的研 究招募了儿童或孕妇。此表显示了随机对照试验的特征。 对于COVID-19重症或危重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局， 鲁索替尼与常规治疗对比的相对效果和绝对效果以及证据确定性评级。关于绝对效果估计值参考的基线风险估计值的来源，见 第7节。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 48 of 119 亚组分析 GDG预设了针对所有关注的JAK抑制剂的几个亚组分析；其中未发现显著的相对亚组效应。详情请参阅巴瑞替尼建议随附 的摘要。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 鲁索替尼 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.87 （95%置信区间 0.27- 2.85） 基于2项研究中 472名参与者的数据 （随机对照） 130 每1000人 115 每1000人 非常低 由于严重的 间接性和 严重的不精确性1 鲁索替尼的效果 非常不确定。 差异：每1000人减少15例 （95%置信区间减少91例-增加169例） 机械通气 优势比0.87 （置信区间95% 0.36- 2.04） 基于2项研究中472名 参与者的数据。 （随机对照） 116 每1000人 108 每1000人 非常低 由于严重的 间接性和 严重的不精确性2 鲁索替尼的效果 非常不确定。 差异：每1000人减少8例 （95%置信区间减少71例-增加94例） 导致停药的 不良反应 基于484项研究中 1名患者的数据。 （随机对照） 0 每1000人 5 每1000人 低 因严重的 不精确性3 鲁索替尼不会造成 导致停药的不良 反应的显著增加。 差异：每1000人增加2例 （95%置信区间增加0例-增加15例） 住院时长 基于1项研究中 484名患者的数据。 （随机对照） 12.8 天（中位数） 11.4 天（均值） 很低 由于严重的 间接性和 严重的不精确性4 鲁索替尼对住院时 长的影响非常 不确定。 差异：平均差增加0.1天 （95%置信区间减少2.1例-增加2.4例） 机械通气时长 越低越好 基于1项研究中3名参 与者的数据。 （随机对照） 14.7 天（中位数） 很低 数据不足5 鲁索替尼对机械通气 时长的作用未知。 临床稳定 所需时间 越低越好 基于2项研究中472名 参与者的数据 （随机对照） 9.9 天（中位数） 9.8 天（均值） 很低 由于严重的 间接性和 非常严重的不精确6 鲁索替尼对临床稳定 所需时间的影响 非常不确定。 差异：平均差减少0.1天 （95%置信区间减少2.5例-增加2.8例） 1. 间接性：严重。大多数患者很可能没有接受基线皮质类固醇治疗。联合使用皮质类固醇可增强白细胞介素-6受体阻滞剂 的有益作用。白细胞介素-6位于JAK路径的下游。因此，假如大多数患者接受类固醇治疗，鲁索替尼的作用可能更大。 此外，鲁索替尼试验可能包括许多患有不严重疾病的患者。JAK抑制剂的有益作用可能仅限于重症或危重症的患者。不 精确性：非常严重。可信区间包括重要利益和重要危害。 2. 间接性：严重。大多数患者很可能没有接受基线皮质类固醇治疗。联合使用皮质类固醇可增强白细胞介素-6受体阻滞剂 的有益作用。白细胞介素-6位于JAK路径的下游。因此，假如大多数患者接受类固醇治疗，鲁索替尼的作用可能更大。 此外，鲁索替尼试验可能包括许多患有不严重疾病的患者。JAK抑制剂的有益作用可能仅限于重症或危重症的患者。不 精确性：非常严重。可信区间包括重要利益和重要危害。 3. 不精确性：非常严重。在报告这一结果的单项试验中，参加该研究的424名患者只有一个事件。 4. 间接性：严重。大多数患者很可能没有接受基线皮质类固醇治疗。联合使用皮质类固醇可增强白细胞介素-6受体阻滞剂 的有益作用。白细胞介素-6位于JAK路径的下游。因此，假如大多数患者接受类固醇治疗，鲁索替尼的作用可能更大。 此外，鲁索替尼试验可能包括许多患有不严重疾病的患者。JAK抑制剂的有益作用可能仅限于重症或危重症的患者。不 精确性：非常严重。可信区间包括重要利益和重要危害。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 49 of 119 5. 偏倚风险：严重。间接性：严重。不精确性：非常严重。 6. 间接性：严重。大多数患者很可能没有接受基线皮质类固醇治疗。联合使用皮质类固醇可增强白细胞介素-6受体阻滞剂 的有益作用。白细胞介素-6位于JAK路径的下游。因此，假如大多数患者接受类固醇治疗，鲁索替尼的作用可能更大。 此外，鲁索替尼试验可能包括许多患有不严重疾病的患者。JAK抑制剂的有益作用可能仅限于重症或危重症的患者。不 精确性：非常严重。可信区间包括重要伤害和重要益处（使用1天作为最小重要差异阈值）。 临床问题/PICO 对象：巴瑞替尼用于COVID-19重症或危重症患者 干预：托法替尼 对照：标准治疗 摘要 证据摘要 对托法替尼进行的LNMA参考了1个随机对照试验，该试验共招募了289名非重症、重症和危重症亚组的患者(67)。该试验已 登记并发表在同行评议的期刊上；试验排除了儿童和孕妇。此表显示了随机对照试验的特征。 对于COVID-19重症或危重症患者，建议分级的评估、制定和评价(GRADE)的结论摘要表显示了对于人们关注的结局，托法 替尼与常规治疗对比的相对效果和绝对效果，以及证据确定性评级。关于绝对效果估计值参考的基线风险估计值的来源，见第7 节。 亚组分析 GDG预设了针对所有关注的JAK抑制剂的几个亚组分析；其中，未发现显著的相对亚组效应。详情请参阅巴瑞替尼建议随附 的摘要。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 托法替尼 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.47 （95%置信区间 0.11- 1.63） 基于1项研究中289名 参与者的数据。 （随机对照） 130 每1000人 78 每1000人 很低 因严重的不精确性1 托法替尼的效果 不确定。 差异：每1000人少52例 （95%置信区间减少113例-增加69例） 机械通气 优势比0.5 （95%置信区间 0.17- 1.37） 基于1项研究中289名 参与者的数据。 （随机对照） 116 每1000人 68 每1000人 很低 因严重的不精确性2 托法替尼的效果 不确定。 差异：每1000人减少48例 （95%置信区间减少94例-增加35例） 导致停药的 不良反应 基于1项研究中284名 参与者的数据。 （随机对照） 0 每1000人 77 每1000人 低 因严重的不精确性3 托法替尼可能增加 导致停药的 不良反应。 差异：每1000人增加77例 （95%置信区间增加17例-增加138例） 住院时长 越低越好 基于1项研究中 289名参与者的数据 （随机对照） 12.8 天（中位数） 11.7 天（均值） 低 因非常严重的 不精确性4 托法替尼可能减少 机械通气的时长。 差异：平均差减少1.1天 （95%置信区间减少2.8例-增加0.6例） 机械通气 时长 14.7 天（中位数） 很低 无数据 托法替尼对机械 通气时长的影响 尚不清楚。 临床稳定 所需时间 9.9 天（中位数） 很低 无数据 托法替尼对临床稳定 所需时间的 作用未知。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 50 of 119 1. 不精确性：极为严重。可信区间包括重要利益和重要危害。总共只有12次事件。 2. 不精确性：极为严重。可信区间包括重要利益和重要危害。总共只有12次事件。 3. 不精确性：非常严重。事件很少：总共只有21次（托法替尼组为16/142，安慰剂组为5/142）。 4. 不精确性：非常严重。可信区间内无重要差异。 6.7.1. 作用机制 I型和II型细胞因子受体是受50多种白细胞介素，干扰素，集落刺激因子和激素使用的受体家族(68)。由这些受体触发的细胞内 信号传导由Janus激酶（JAKs）介导，JAKs是激酶的一个小家族，包括JAK1，JAK2，JAK3和酪氨酸激酶2（TYK2）。I型细胞因 子包括 IL-2、IFN-γ、IL-12 和 TNFb，II型细胞因子包括 IL-4、IL-5、IL-6、IL-10 和 IL-13。 JAK抑制剂是一类通过对细胞因子信号传导的多因素作用来抑制细胞内信号传导的药物。因此，它们会干扰许多细胞反应， 包括抗病毒反应，血管紧张素转换酶2(ACE2)表达，T细胞功能和分化以及巨噬细胞活化(68)。 巴瑞替尼、鲁索替尼和托法替尼是至少9种JAK抑制剂中的三种。这三种药物通常都被认为是非特异性JAK抑制剂，但不同 JAK之间的特异性和效力差异是明显的。巴瑞替尼被描述为JAK1/JAK2抑制剂，鲁索替尼作为JAK1/JAK2>TYK2，托法替尼作为 JAK3/JAK1>JAK2/TYK2；其他差异也已在上文描述过(68)(69)(70)。 已就JAK抑制剂用于治疗COVID-19进行评估研究，其剂量与批准用于其他适应症（如类风湿性关节炎，骨髓纤维化和溃疡性 结肠炎）的剂量相同或更高。因此，合理性取决于在COVID-19中细胞因子信号传导的作用，而不是取决于研究剂量下的药代动力 学是否足以抑制靶蛋白。在批准剂量、时间表、药代动力学、禁忌症以及其他适应症方面，这些药物存在显著差异。综合这些差 异，基于当前可用数据进行全类推荐的信心受限。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 51 of 119 6.8. 索托维单抗（2022年1月14日发布） 信息栏 2022年1月14日，关于COVID-19重症和非重症患者使用索托维单抗的建议作为世卫组织动态指南第八版发布，并在《英国 医学杂志》上作为快速建议发表。指南在LNMA提供了一项关于抗体和细胞疗法的非重症随机对照试验之后制定(2)。在本第十 一版指南中，没有修订索托维单抗的建议。 GDG目前正在评估日渐主导的奥密克戎BA.2变异株在多大程度上显著降低了索托维单抗的临床疗效，现阶段临床前体外数 据显示了这种疗效的降低（见“作用机制”）。GDG还指出，对于住院风险最高的非COVID-19重症患者，有几种替代治疗方 案（见第6.1节和建议下的备注）。 用于住院风险最高的COVID-19非重症患者 有条件建议使用 我们建议使用索托维单抗治疗（有条件建议使用）。 • 关于识别住院风险最高患者的帮助，参见第6.1节。 • 有几种治疗方案可供选择：参见决策支持工具，该工具列出了奈玛特韦-利托那韦、莫努匹拉韦、瑞德西韦和单克隆 抗体（包括索托维单抗和卡西维单抗-伊德维单抗）的利弊。 • GDG得出结论，奈玛特韦-利托那韦可能是一种更优的选择，因为它在预防住院方面可能比替代药物具有更大的疗 效，对于其危害的关切少于莫努匹拉韦，并且比静脉注射瑞德西韦和抗体更容易给药。 • 奥密克戎BA.2变异株可能会大大降低索托维单抗的临床疗效；GDG目前正在评估这个问题。 • COVID-19重症或危重症患者：根据现有证据，索托维单抗对COVID-19重症或危重症血清阴性患者的益处尚不清楚 （见第6.10节中的卡西瑞单抗-伊德维单抗建议）。这意味着，如果卡西瑞单抗不可用并且考虑索托维单抗，需进行仔 细的临床判断。 实用信息 途径、剂量和疗程：其他考虑因素参见实用问题的相关摘要。以下是关键要点的简明摘要： • 索托维单抗的授权剂量是单次30分钟静脉输注500mg，在SARS-CoV-2病毒检测阳性后并在出现症状后10天内尽快给药。 • 索托维单抗以浓缩溶液的形式提供，必须在给药前稀释。 • 患者在输注过程中应接受临床监测，并在输注完成后观察至少1小时。 决策证据 利弊 在非重症患者中，索托维单抗很可能减少住院治疗，对输注反应几乎没有影响，没有关于临床改善所需时间的数据。索托维 单抗很可能对死亡率和机械通气几乎没有影响。 由于缺乏公开报告或由调查人员提供的亚组数据，无法进行原计划的亚组分析。 证据的确定性 证据摘要参考一项随机对照试验，包括LNMA中的1057名患者(COMET-ICE) (74)。该试验提供了中等确定性的（由于严重的 不精确性）减少住院治疗证据，高确定性的无输注反应证据，中等确定性的（由于严重间接性）死亡率无或小差异证据，低确定 性的（由于严重间接性和不精确性）机械通气无或小差异证据。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 52 of 119 现有基于实证开发的、用以确定患者住院风险的风险预测工具存在局限性，这是导致GDG调低证据确定性评级的间接性的主 要来源。此外，GDG认为一些间接性的原因是，可能出现一些变异株使当前可用的单克隆抗体的疗效降低。 在评价精确度时，GDG考虑了绝对风险的估计值。因此，在事件发生率很低（例如，非重症患者死亡风险很低）的背景下， 尽管存在相对风险和较宽的置信区间，但GDG并未因不精确而降低评级。 价值观和偏好 应用议定的价值观和偏好（见第7节），GDG推断，几乎所有充分知情的、低住院风险的患者都会拒绝使用索托维单抗，只有 风险最高的患者（如未接种疫苗、老年人或免疫抑制的患者）会选择接受治疗。 在缺乏研究证据的情况下，在之前的一项调查中（参见卡西瑞单抗-伊德维单抗的建议），GDG表达了这样一种观点，即大多 数住院风险超过10%、因而绝对风险可降低6%的患者，会选择接受治疗，而大多数低于该风险水平的患者会拒绝治疗。这里也使 用了这些阈值。 资源和其他考虑因素 可接受性和可行性 GDG注意到，所有愿意选择接受此疗法的人不太可能都能获得索托维单抗。这进一步支持了索托维单抗应留给住院风险最高 患者的指导意见。 其他挑战包括要求通常在家接受治疗的患者接受静脉注射。可能需要专业诊所来确保安全有效地管理索托维单抗。要想大量 使用这种干预措施，卫生保健系统必须解决这些挑战。 鉴于索托维单抗的成本和可用性，确保低收入和中等收入国家获得该治疗的障碍可能是巨大的。例如，在出现症状的最初5 天，社会经济的弱势群体获得服务的频次往往较少），因而少有机会获取干预措施。因此，小组作出的由风险最高的患者接受干 预的建议可能会加剧卫生不公平。另一方面，鉴于对患者已证明的益处，以及一些低收入和中等收入国家以及低收入国家(LICs)的 疫苗覆盖率仍然很低，索托维单抗可能是减少未接种疫苗人群因COVID-19住院的有用工具。本建议应能激励调动所有可能的机制 参与改善此干预措施的全球可及性。各国可根据可用资源制定自己的指南，并相应地确定治疗方案的优先次序。2021年12月17 日，世卫组织发布了第7次邀请，请COVID-19疗法制造商向世卫组织预认证部门提交产品评估意向书(EOI)，其中包括索托维单 抗。 理由 结合证据，价值观和偏好以及可行性，提出了仅在住院风险最高的COVID-19非重症患者中使用索托维单抗的有条件建议。最 高风险人群的典型特征包括未接种疫苗者、老年人或存在免疫缺陷和/或慢性疾病（例如糖尿病）的患者。 尽管有中等确定性证据表明可大幅降低住院的相对风险，但只有少数属于风险最高的患者才有可能获得足够的益处，以弥补 此疗法的风险以及其他局限性和缺点。这些局限性包括缺乏可靠的工具来识别高危患者，为通常在社区接受治疗的患者提供肠外 治疗，以及有限的药物可用性。 索托维单抗与卡西瑞单抗-伊德维单抗的相互关系 另一种单克隆抗体组合卡西瑞单抗-伊德维单抗也被有条件地建议用于住院风险最高的非重症 COVID-19患者。GDG建议临床 医生不要同时给药，因为缺乏证据表明同时给药会产生增量益处，并且从机理上看，获得增量益处的可能性很低。 然后，GDG考虑了如何在两种药物之间进行选择。没有试验提供了头对头的比较。根据LNMA的间接比较（见研究证据中的 GRADE结果摘要表），对于阿尔法和德尔塔变异株，药物对关键结局的影响可能几乎没有差异。 目前和将来，单克隆抗体的选择将取决于在药物针对不同变异株的有效性方面的新信息和药物的可获得性，以及临床和背景 因素。值得注意的是，LNMA中包含的随机对照试验是在奥密克戎变异株出现之前进行的。 在先前发表对卡西瑞单抗-伊德维单抗的有条件建议之后，临床前证据表明，这对单克隆抗体组合在体外缺乏对奥密克戎变异 株的中和活性(71)。最近的临床前数据表明，索托维单抗对日渐主导的奥密克戎BA.2变异株的中和活性大大降低（参见“作用机 制”）。在缺乏临床证据的情况下，其对索托维单抗疗效的影响尚不清楚，目前GDG正在进行评估。 适用性 儿童和孕妇：纳入的随机对照试验仅招募非怀孕成年人；鉴于此，对儿童和孕妇的适用性尚不确定。GDG没有理由相信患有 COVID-19的儿童或孕妇对索托维单抗治疗的反应会有所不同。然而对儿童来说，住院的风险通常极低，因此GDG推断，除非存在 免疫抑制或其他重大风险因素，不应对儿童使用此干预措施。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 53 of 119 COVID-19重症和危重症：一项随机对照试验将546名因COVID-19住院的成年人随机分配到两种中和单克隆抗体疗法组（索托 维单抗和BRII-196加BRII-198）或安慰剂组(73)。结果没有证明这些抗体疗法的益处，包括对血清阳性与血清阴性患者的亚组分 析。虽然索托维单抗在COVID-19重症和危重症中的作用没有得到新试验的支持，但GDG并未对其进行评估，因为小组关注的是在 制定建议时有可用证据的COVID-19非重症患者；GDG将充分考虑该试验以及任何其他可公开获得的新证据，以便未来制定索托维 单抗的建议。 临床问题/PICO 对象：COVID-19非重症患者 干预：索托维单抗 对照：标准治疗 摘要 索托维单抗的LNMA参考了一项随机对照试验(COMET-ICE)对1057名有症状（症状出现后不超过5 天）且至少有一个疾病 进展危险因素的COVID-19非住院患者进行了随机调查。在1057名随机患者中，LNMA团队可以访问1044名患者的数据。纳入的 患者被随机分配接受单次输注500mg剂量的索托维单抗或安慰剂。患者中位年龄为53岁；46%是男性。意向治疗人群的随访中 位数时间为72天。已接种疫苗的患者被排除在试验之外(74)。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，索托维单抗与标准治疗（安慰剂）相 比的相对效果和绝对效果，并给出了证据确定性评级。 亚组分析 GDG要求进行四项预设的亚组分析： 1. 年龄：儿童对比成年人（不足70岁）对比老年人（70岁及以上）。 2. 治疗开始时的疾病严重程度：非重症、重症、危重症。 3. 出现症状的时间 4. 血清学状态 试验中没有数据可用于进行这些分析。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 索托维单抗 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.11 （95%置信区间 0-2.6） 基于1项研究中1044名 患者的数据。 （随机对照） 6 每1000人 1 每1000人 中等 因严重的间接性和 有关不精确性的 一些担忧1 索托维单抗很可能 对死亡率几乎 没有影响。 差异：每1000人减少5例 （95%置信区间减少6例-增加9例） 机械通气 优势比0.11 （95%置信区间 0- 2.6） 基于1项研究中1044名 参与者的数据。 （随机对照） 8 每1000人 1 每1000人 低 由于严重的间接性 和关于不精确性的 一些担忧2 索托维单抗很可能 对机械通气几乎 没有影响。 差异：每1000人减少7例 （95%置信区间减少8例-增加13例） 住院 试验中的风险 优势比0.19 （95%置信区间 0.06-0.51） 基于1项研究中1044名 参与者的数据。 （随机对照） 35 每 1000人 7 每 1000人 中等 因严重的不精确性3 索托维单抗很可能会 减少住院。 差异：每 1000 人减少 28 例 （95%置信区间减少33例-减少17例） 住院 较高风险 优势比0.19 （95%置信区间 60 每 1000人 12 每 1000人 中等 因严重的不精确性4 索托维单抗很可能会 减少住院。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 54 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 索托维单抗 证据的确定性 （证据质量） 纯文本摘要 0.06-0.51） 基于1项研究中1044名 参与者的数据。 （随机对照） 差异：每1000人减少48例 （95%置信区间减少56例-减少28例） 住院 最高风险 优势比0.19 （95%置信区间 0.06-0.51） 基于1项研究中1044名 参与者的数据。 （随机对照） 100 每1000人 21 每1000人 中等 因严重的不精确性5 索托维单抗很可能会 减少住院。 差异：每1000人减少79例 （95%置信区间减少93例 – 减少46例） 输注反应 基于1项研究中1044名 参与者的数据。 （随机对照） 0 每1000人 0 每1000人 高 索托维单抗几乎 没有导致输注 反应的增加。 差异：每1000人减少0例 （95%置信区间减少13例-增加13例） 临床改善 所需时间 无数据 索托维单抗的 作用未知。 1. 死亡率将非常小。有些人的基线风险要高得多，这些人不容易识别。对于这些患者，索托维单抗可能对死亡率有重要影 响。不精确性：不严重。在研究索托维单抗的单项试验中，只有四例死亡（均在安慰剂组）。 2. 间接性：严重。整个人群的基线风险很低，这意味着对死亡率的任何影响都将非常小。有些人的基线风险要高得多，这 些人不容易识别。对于这些患者，索托维单抗可能对机械通气有重要影响。不精确性：严重。事件很少 - 在单项试验 中，只有四名患者接受了有创机械通气（均在安慰剂组）。 3. 不精确性：严重。事件很少（总共25例：索托维单抗组4例，安慰剂组21例）；未达到最优信息样本量。 4. 不精确性：严重。事件很少（总共25例：索托维单抗组4例，安慰剂组21例）；未达到最优信息样本量。 5. 不精确性：严重。事件很少（总共25例：索托维单抗组4例，安慰剂组21例）；未达到最优信息样本量。 临床问题/PICO 对象：COVID-19非重症患者 干预：索托维单抗 对照：卡西瑞单抗-伊德维单抗 结局 时限 研究结果和衡量标准 对照组 卡西瑞单抗- 伊德维单抗 干预组 索托维单抗 证据的确定性 （证据质量） 纯文本摘要 机械通气 优势比0 （95%置信区间0-0.01） （随机对照） 2 每1000人 0 每1000人 中等 因严重的间接性和 对于不精确性的 一些关切2 机械通气方面 很可能几乎 没有差异。 差异：每1000人减少2例 （95%置信区间减少2例-减少2例） 死亡率 优势比0.53 （95%置信区间 0.09-2.12） （随机对照） 3 每1000人 2 每1000人 中等 因严重的间接性和 关于不精确性的 一些关切1 死亡率方面很可能 几乎没有差异。 差异：每1000人减少1例 （95%置信区间减少3例-增加3例） 差异：每1000人减少4例 （95%置信区间减少4例-减少0例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 55 of 119 结局 时限 研究结果和衡量标准 对照组 卡西瑞单抗- 伊德维单抗 干预组 索托维单抗 证据的确定性 （证据质量） 纯文本摘要 住院 较高风险 优势比0.68 （95%置信区间 0.21-1.97） （随机对照） 18 每1000人 12 每1000人 中等 因严重的间接性和 关于不精确性的 一些关切3 住院方面很可能 几乎没有差异。 差异：每1000人减少6例 （95%置信区间减少14例-增加17例） 输液反应 （随机对照） 0 每1000人 0 每1000人 高 输注反应方面几乎 没有差异。 差异：每1000人减少0例 （95%置信区间减少13例-增加13例） 住院 最高风险 优势比0.68 （95%置信区间 0.21-1.97） （随机对照） 31 每1000人 21 每1000人 中等 因严重的间接性和 关于不精确性的 一些关切3 住院方面很可能 几乎没有差异。 差异：每1000人减少10例 （95%置信区间减少24例-增加28例） 住院 试验中的风险 优势比0.68 （95%置信区间 0.21-1.97） （随机对照） 10 每1000人 7 每1000人 中等 因严重的间接性和 关于不精确性的 一些关切3 住院方面很可能 几乎没有差异。 差异：每1000人减少3例 （95%置信区间减少8例-增加10例） 临床改善 所需时间 无数据 索托维单抗的 作用未知 • 间接性：严重。整个人群的基线风险很低，意味着对机械通气的任何影响都将非常小。有些人的基线风险要高得多，但 不容易识别。对于这些患者而言，机械通气方面是否存在重要差异尚不确定。不精确性：不严重。事件很少——在该单 项试验中，只有两名患者接受了介入性机械通气（均在安慰剂组）。 • 间接性：严重。整个人群的基线风险很低，这意味着对死亡率的任何影响都将非常小。有些人的基线风险要高得多，但 不容易识别。对于这些患者，治疗对死亡率的影响尚不确定。不精确性：不严重。事件很少 - 在研究索托维单抗的单项 试验中，只有1例死亡（在安慰剂组）。 • 间接性：严重。高危患者不易识别。不精确性：不严重。 • 间接性：严重。高危患者不易识别。不精确性：不严重。 • 间接性：严重。高危患者不易识别。不精确性：不严重。 6.8.1. 作用机制 索托维单抗（VIR-7831；GSK4182136）是一种单一的人源单克隆抗体，可与SARS-CoV-2刺突蛋白的保守表位结合，防止病 毒进入细胞。 索托维单抗是一种Fc工程的IgG单克隆抗体，预计其半衰期比未改造的IgG单克隆抗体长，但没有关于其在人体中半衰期的公 开数据。没有已发表的临床前或人类药代动力学数据可供审查；因此，评估基于公共监管信息和葛兰素史克的产品专论(75)。 在感染SARS-CoV-2的叙利亚金黄地鼠模型中，在5毫克/公斤IP下证明了抗病毒活性，但使用的抗体版本不是Fc工程的(75)。 在Vero E6细胞中实现了SARS-CoV-2(USA WA1/2020)的中和，EC90值为0.19微克/毫升(76)。COMET-ICE中的索托维单抗血清浓度 （单次500毫克静脉输注）提供几何平均Cmax（在1小时静脉输注结束时）为117.6微克/毫升（N=129，CV% 40）以及第29天几何 平均血清浓度为24.5微克/毫升(76)。因此，预计29天后，人群平均血清浓度将是体外中和SARS-CoV-2原始菌株所需的浓度的129 倍。 来自Vir 生物技术的作者的一篇综述手稿表明，对于所有测试的受关注变异株（当时不包括奥密克戎），索托维单抗的中和损 失不到10倍(77)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 56 of 119 美国食品和药物管理局紧急使用授权中的信息还声明，在伪型病毒样颗粒中和测定中，索托维单抗对阿尔法，贝塔，伽马， 艾普西隆，约塔，卡帕，德尔塔（包括K417N），拉姆达和缪的活性“无变化”(76)。据报道，索托维单抗在假病毒测定中保持对 奥密克戎BA.1的活性，但与野生型病毒相比，中和需要更高的浓度(72)。几份报告显示，其对奥密克戎亚谱系BA.2的中和作用所 受的影响比对BA.1更严重。1 (79)(78) (https://www.biorxiv.org/content/10.1101/2021.03.09.434607v10)。需要更好地了解药代动力学 - 药效学关系，以确定此类活性的降低对索托维单抗疗效的影响。 在细胞培养物中索托维单抗的选择压力下，刺突蛋白保守表位中迅速出现了E340A氨基酸替换，随后使用假病毒测定的表征 结果是对索托维单抗的敏感性降低超过100倍(76)。进入表位的其他16种替换也被描述为使索托维单抗的中和减少5.4倍至超过297 倍(76)。因此，在实验条件下可出现对索托维单抗的耐药性。此外，据报道，在澳大利亚德尔塔传播潮中接受索托维单抗治疗的最 初连续1000例患者中，有4例在其病毒序列中出现了E340突变，并且培养物在给药后12-24天仍保持阳性(80)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 57 of 119 6.9. 恢复期血浆（2021年12月7日发布） 信息栏 2021年12月7日，关于COVID-19非重症、重症和危重症患者的恢复期血浆的建议作为世卫组织动态指南第七版发布，并在 《英国医学杂志》上作为快速建议发表。指南在关于抗体和细胞疗法的LNMA提供了不同疾病严重程度的16项随机对照试验之 后制定(2)。在本第十一版指南中，未对恢复期血浆的建议进行修改。 用于COVID-19非重症患者 强烈建议不使用 新增 我们建议不要使用恢复期血浆治疗。（强烈建议不使用） 实用信息 GDG强烈建议不使用恢复期血浆治疗COVID-19非重症患者，并建议不要在非临床试验中对COVID-19重症和危重症患者使用 恢复期血浆。因此，我们不会详细论述与恢复期血浆相关的许多实践问题，包括但不限于：潜在供血者的识别与招募、血浆的采 集、血浆的储存和分配，以及给受血者输注恢复期血浆。 决策证据 利弊 在非重症患者中，恢复期血浆不会对死亡率产生重要影响。恢复期血浆很可能不会对机械通气产生影响。没有关于恢复期血 浆对住院风险影响的评估数据，因此在这方面的影响非常不确定。 恢复期血浆很可能不会导致输血相关性急性肺损伤（TRALI）、输血相关循环超负荷（TACO）或过敏反应风险的显著增加。 证据的确定性 死亡率的证据确定性为高，而由于严重的偏倚风险，机械通气的证据确定性被定为中等。由于存在严重的偏倚风险，输血相 关性急性肺损伤和输血相关循环超负荷的确定性被评为中等，由于担忧偏倚风险和不精确性，过敏反应的证据确定性被评为中 等。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG推断，几乎所有完全知情的患者都会根据关于相对利弊的现有证据，选择不 接受恢复期血浆进行治疗。从人群角度来看，可行性、可接受性、公平和成本是需要考虑的其他重要因素（见第7节）。 对于非重症患者，GDG认为资源和可行性问题在门诊环境中可能更大，大规模调动恢复期血浆的使用的可行性恐怕值得怀 疑。 资源和其他考虑因素 可接受性和可行性 GDG指出，恢复期血浆的使用需要配以大量的资源，包括识别潜在的供血者、对供血者进行检测以确保抗SARS-CoV-2抗体 具有足够的滴度、采集供血者血浆、储存血浆、将血浆运输到受血者所在地以及血浆输注。这些资源和可行性问题对于那些在门 诊中占大多数的非重症患者来说十分复杂。此外，这一治疗过程成本高、耗时长。考虑到非重症患者的数量大且该亚组患者的事 件发生率低，大规模调动恢复期血浆的使用的可行性值得怀疑。 虽然输血对大多数人来说是可以接受的，但也有一部分人不接受异体输血。在大多数司法管辖区，还存在与血液制品输注相 关的监管挑战。 理由 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 58 of 119 证据、价值观和偏好以及可行性结合在一起，促成了对COVID-19非重症患者不使用恢复期血浆的强烈建议。最重要的是，鉴 于对COVID-19非重症或危重症或重症患者的任何关键或重要结局都没有显示出益处，GDG认为没有理由耗费资源（包括时间和成 本）使用恢复期血浆进行治疗。建议还考虑了可能的相关危害（尽管在证据摘要中没有说明，但血液制品输注总是存在潜在危 害）、非重症患者的基线死亡率、机械通气和住院风险低的情况，以及使用恢复期血浆的可行性方面的挑战。 滴度 不同被纳入的试验使用的中和抗体滴度差异很大，超过一半的试验根本没有报告或考虑受血者滴度。事实上，最大的试验 （“康复”试验）根本没有报告供血者的抗体滴度。即使报告了滴度，测定方法和输注的血浆量也各不相同。因此不可能根据供 血者滴度水平进行分析或进行的可信亚组效应的评估。 适用性 本建议对儿童和孕妇的适用性目前尚不确定，因为所纳入的随机对照试验招募的都是没有怀孕的成年人。GDG不认为COVID- 19患儿对恢复期血浆治疗会有任何不同的反应。然而，儿童的住院风险通常极低，GDG推断在没有免疫抑制或其他重大风险因素 的情况下，儿童不应接受此干预措施。 临床问题/PICO 对象：COVID-19非重症患者 干预：恢复期血浆 对照：标准治疗 摘要 证据摘要 对恢复期血浆进行的LNMA纳入了16个随机对照试验，共招募了16236名非重症、重症和危重症亚组的患者。所有随机对照 试验均已登记，其中80%的试验发表在同行评议的期刊上；20%发布了预印本。99%的参与者为住院患者；其中15%在重症监护 室（ICU）接受治疗。1%的患者从门诊招募。没有一项研究招募了儿童或孕妇。此表列出了随机对照试验的特征，其中两项试验 使用血浆替代品作为安慰剂，没有被包括在证据摘要中。我们知晓另有两个已发表的随机对照试验将恢复期血浆与标准治疗或安 慰剂进行了比较(81)(82)，但这两个试验没有被纳入提交给GDG的、形成本建议基础的最新分析中。 对于COVID-19非重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，恢复期血 浆与常规治疗对比的相对效果和绝对效果，并显示了证据确定性评级。作为证据摘要基础的LNMA(2)汇总了4个随机对照试验中 1602名患者的死亡率结局数据，除过敏反应外（8个随机对照试验，243名患者），其他结局的可用数据较少。参阅第7节了解影 响绝对效果估计值的基线风险估计值的来源。 亚组分析 我们预先指定了对以下相关亚组进行分析： 1. 年龄：年轻成年人（不足 70岁）对比老年人（70岁以上）。 2. 疾病严重程度（治疗开始时）：非重症对比重症和危重症。 3. 治疗剂量：高滴度血浆对比低滴度血浆。 对所有疾病严重程度的患者进行了亚组分析。大多数亚组没有足够的数据从而对感兴趣的结局进行亚组分析。 在有足够数据的亚组中，我们发现疾病严重程度（p=0.80）和年龄（p=0.84）对死亡率没有显著的亚组效应，疾病严重程度 （p=0.17）对机械通气没有显著的亚组效应。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 59 of 119 结局 时限 研究结果和 衡量标准 对照组 标准治疗 干预组 使用恢复期血浆 证据的确定性 （证据质量） 纯文本摘要 死亡率 最接近 90天 优势比 0.83 （95%置信区间 0.43-1.46） 基于 4项研究中 1602名患者的数据 1 （随机对照） 3 每 1000人 2 每 1000人 高 2 恢复期血浆对 死亡率没有 重要影响。 差异：每 1000 人减少 1 例 (95%置信区间减少 2例—增加 1例) 机械通气 最接近 90天 优势比 0.71 （95%置信区间 0.18-1.77） 基于 3项研究中 705名患者的数据 3 （随机对照） 6 每 1000人 4 每 1000人 中等 由于严重的 偏倚风险 4 恢复期血浆很可能 对机械通气没有 影响。 差异：每 1000 人减少 2 例 （95%置信区间减少 5例—增加 5例） 输血相关性急性 肺损伤（TRALI） 28天内 基于 4项研究中 1365名患者的数据 5 （随机对照） 0 每 1000人 0 每 1000人 中等 由于严重的 偏倚风险 6 恢复期血浆很可能 不会导致输血相关 性急性肺损伤 显著增加。 差异：每 1000 人减少 0 例 （95%置信区间减少 5例—增加 6例） 输血相关循环 超负荷（TACO） 28天内 基于 4项研究中 1442名患者的数据 7 （随机对照） 0 每 1000人 5 每 1000人 中等 由于严重的 偏倚风险 8 恢复期血浆很可能 不会导致输血相关 循环超负荷的 显著增加。 差异：每 1000 人增加 5 例 （95%置信区间减少 3例—增加 12例） 过敏反应 28天内 优势比 3.25 （95%置信区间 1.27-9.3） 基于 8项研究中 15243名患者的 数据 9 （随机对照） 3 每 1000人 10 每 1000人 低 由于对偏倚风险和 不精确性的担忧 10 恢复期血浆很可能 不会导致过敏反应的 显著增加。 差异：每 1000 人增加 7 例 （95%置信区间增加 1例—增加 24例） 1. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[87], [83], [84], [86]。 2. 偏倚风险：不严重。GDG没有因缺乏盲法导致的偏倚风险而降低评级。 3. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[83], [84], [87]。 4. 偏倚风险：严重。不精确性：不严重。GDG没有因为不精确性而降低评级，因为可信区间排除了一个重要益处和重要危 害。 5. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[88], [84], [89], [85]。 6. 偏倚风险：严重。大多数患者被招募至非盲研究。不精确性：不严重。GDG决定不因不精确性而降低评级，因为可信区 间排除了一个重要效果，而且基线风险很低。 7. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[89], [85], [83], [88]。 8. 偏倚风险：严重。大多数患者被招募至非盲研究。不精确性：不严重。GDG决定不因不精确性而降低评级，因为可信区 间排除了一个重要效果，而且基线风险很低。 9. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[92], [88], [86], [83], [91], [85], [89], [90]。 10. 偏倚风险：严重。2 项试验（491 名患者；占总数的 3%）的偏倚风险低，而 6 项试验（14 910 名患者）的偏倚风险高。 不精确性：严重。GDG一致认为可信区间包含一些对过敏反应的担忧，尽管也承认基线风险低。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 60 of 119 用于COVID-19重症或危重症患者 仅在研究环境中 新增 我们建议不要使用恢复期血浆治疗 COVID-19，除非在临床试验中。（仅在研究环境中建议使用） 实用信息 GDG建议不要在非临床试验中使用恢复期血浆治疗COVID-19重症或危重症患者，并强烈建议不要使用恢复期血浆治疗 COVID-19非重症患者。因此，我们不会详细论述与恢复期血浆相关的许多实践问题，包括但不限于：潜在供血者的识别与招募、 血浆的采集、血浆的储存和分配，以及给受血者输注恢复期血浆。 决策证据 利弊 对于重症或危重症患者，恢复期血浆可能不会对死亡率、机械通气、症状改善时间、住院时间或无呼吸机天数产生重要影 响。 恢复期血浆很可能不会导致输血相关性急性肺损伤、输血相关循环超负荷或过敏反应的风险显著增加。然而，尽管证据摘要 中没有说明，但血液制品输注总会存在潜在危害。 证据的确定性 由于对间接性、偏倚风险和不精确性的担忧，死亡率的证据确定性评为低。因为存在严重的偏倚风险和严重的不精确性， GDG将机械通气、住院时间和无呼吸机天数的确定性下调为低，因为非常严重的不精确性，将症状改善时间的证据确定性下调为 低。 由于存在严重的偏倚风险，输血相关性急性肺损伤和输血相关循环超负荷的证据确定性被评为中等，由于对偏倚风险和不精 确性的担忧，过敏反应的证据确定性被评为中等。 偏好与价值观 根据一致商定的价值观和偏好（见第7节），GDG推断，几乎所有完全知情的患者都会根据关于相对利弊的现有证据，选择不 接受恢复期血浆进行治疗。从人群角度来看，可行性、可接受性、公平和成本是需要考虑的其他重要因素，详见第7节。 资源和其他考虑因素 可接受性和可行性 GDG指出，恢复期血浆的使用需要配以大量的资源，包括识别潜在的供血者、对供血者进行检测以确保抗SARS-CoV-2抗体 具有足够的滴度、采集供血者血浆、储存血浆、将血浆运输到受血者所在地以及血浆输注。这些资源和可行性问题对于那些在门 诊中占大多数的非重症患者来说十分复杂。此外，这一治疗过程成本高、耗时长。 虽然输血对大多数人来说是可以接受的，但也有一部分人不接受异体输血。在大多数司法管辖区，还存在与血液制品输注相 关的监管挑战。 理由 经过大量讨论，GDG决定建议，除非在临床试验的情况下，不对COVID-19重症或危重症患者使用恢复期血浆。鉴于低确定性 证据表明对死亡率、机械通气和症状改善时间的效果很小或没有效果，以及可能会产生相关危害（尽管在证据摘要中没有表明， 但血液制品的输注总是存在潜在的危害），小组一致认为，针对这些对患者重要的结局进行进一步研究很有价值。这项针对 COVID-19重症或危重症的研究还考虑到了可行性（患者已经住院）和基线死亡率风险，以及对生命支持干预措施的需要（重症/ 危重症的需要更高）。小组将高滴度产品确定为未来研究的最优先事项，并认为有必要报告供血者的滴度和输注量以了解在受血 者体内的滴度稀释情况。同样，小组将血清阴性的COVID-19患者确定为恢复期血浆未来研究的最优先对象。 当证据确定性为低时，建议仅在临床试验中使用该药物是合适的，未来的研究有可能降低关于此干预措施效果的不确定性， 并以合理的成本进行。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 61 of 119 临床问题/PICO 对象： COVID-19重症或危重症患者 干预： 恢复期血浆 对照： 标准治疗 摘要 恢复期血浆的证据摘要 请参见上文对COVID-19非重症患者的摘要。里面有关于LNMA和16个涉及各种疾病严重程度的被纳入的试验的细节，以及 按年龄、疾病严重程度或恢复期血浆剂量进行的亚组分析，但没有发现可信效果。 对于COVID-19重症和危重症患者，建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局， 恢复期血浆与常规治疗对比的相对效果和绝对效果，并显示了证据确定性评级。作为证据摘要基础的LNMA(2)汇总了10项研究 中来自14366名患者的死亡率结局数据，其他结局的可用数据较少。 基线风险估计值 对于重症和危重症的死亡率这一关键结局，应用的基线风险估计值为13%（130/1000）。本指南中的其他相关建议的估计 值来自针对重症和危重症患者的“团结”试验，并根据皮质类固醇的治疗效果进行了调整。对于其他结局，我们使用了形成证 据的随机对照试验中对照组的中位数（见第7节）。 亚组分析 我们预先指定了对以下相关亚组进行分析： 1. 年龄：年轻成年人（小于 70岁）对比老年人（大于 70岁）。 2. 疾病严重程度（治疗开始时）：非重症对比重症和危重症。 3. 治疗剂量：高滴度血浆对比低滴度血浆。 大多数亚组没有足够的相关结局数据来进行亚组分析。 在有足够数据的亚组中，我们发现疾病严重程度（p=0.80）和年龄（p=0.84）对死亡率没有显著的亚组效应，疾病严重程 度（p=0.17）对机械通气没有显著的亚组效应。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 使用恢复期血浆 证据的确定性 （证据质量） 纯文本摘要 死亡率 最接近 90天 优势比 0.92 （95%置信区间 0.7-1.12） 基于 10项研究中 14366名患者的数据 1 （随机对照） 130 每 1000人 121 每 1000人 很低 由于对间接性、 偏倚风险和 不精确性的担忧 2 恢复期血浆 对死亡率可能几乎 没有影响。 差异：每 1000 人减少 9 例 （95%置信区间 减少 35例—增加 13例） 机械通气 最接近 90天 优势比 0.92 （95%置信区间 0.46-1.68） 基于 5项研究中 623名患者的数据 3 （随机对照） 86 每 1000人 80 每 1000人 低 由于严重的偏倚 风险和严重的 不精确性 4 恢复期血浆 对机械通气可能 没有影响。 差异：每 1000 人减少 6 例 （95%置信区间减少 45例—增加 50例） 输血相关性急性 肺损伤 （TRALI） 28天内 基于 4项研究中 1365名患者的数据 5 （随机对照） 0 每 1000人 0 每 1000人 中等 由于严重的 偏倚风险 6 恢复期血浆很可能 不会导致输血相关性 急性肺损伤的 显著增加。 差异：每 1000 人减少 0 例 （95%置信区间减少 5例—增加 6例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 62 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 使用恢复期血浆 证据的确定性 （证据质量） 纯文本摘要 输血相关循环 超负荷(TACO) 28天内 基于 4项研究中 1442名患者的数据 7 （随机对照） 0 每 1000人 5 每 1000人 中等 由于严重的 偏倚风险 8 恢复期血浆很可能 不会导致输血相关 循环超负荷的 显著增加。 差异：每 1000 人增加 5 例 （95%置信区间减少 3例—增加 12例） 过敏反应 28天内 优势比 3.25 （95%置信区间 1.27-9.3) 基于 8项研究中 15243名患者的数据 9 （随机对照） 3 每 1000人 10 每 1000人 低 由于对中等 由于对偏倚风险和 不精确性的担忧 10 恢复期血浆很可能 不会导致过敏反应的 显著增加。 差异：每 1000 人增加 7 例 （95%置信区间增加 1例—增加 24例） 症状改善时间 越低越好 基于 3项研究中 472名患者的数据 11 （随机对照） 15 （均值） 15 （均值） 低 由于非常严重的 不精确性 12 恢复期血浆对症状 改善时间可能 没有影响。 差异：平均差减少0 （95%置信区间减少 10.4—增加 33.6） 住院时间 度量单位：天数 越低越好 基于 7项研究中 1015名患者的数据 13 （随机对照） 11.7 天（平均） 11 天（平均） 低 由于严重的偏倚风险 和严重的不精确性 14 恢复期血浆 对住院时间可能 没有影响。 差异：平均差减少0.7天 （95%置信区间减少 2.3天—增加 1天） 无呼吸机天数 28天内 度量单位：天数 越高越好 基于 3项研究中： 2859名患者的数据 15 （随机对照） 13.7 天（平均） 13 天（平均） 低 由于严重的偏倚风险 和严重的不精确性 16 恢复期血浆 对无呼吸机天数可能 没有影响。 差异：平均差减少0.7天 （95%置信区间减少 1.8天—增加 0.4天） 1. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[89], [93], [95], [92], [90], [88], [94], [86], [96], [91]。 2. 偏倚风险：严重。间接性：严重。不精确性：严重。可信区间包含了重要益处和重要危害。 3. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[93], [89], [85], [92], [95]。 4. 偏倚风险：严重。不精确性：严重。GDG决定可信区间由于不精确性而只降级一次。 5. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[85], [89], [84], [88],。 6. 偏倚风险：严重。大多数患者被招募至非盲研究。不精确性：不严重。GDG决定不因不精确性而降级，因为可信区间排 除了一个重要效果，而且基线风险低。 7. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[88], [83], [89], [85]。 8. 偏倚风险：严重。大多数患者被招募至非盲研究。不精确性：不严重。GDG决定不因不精确性而降级，因为可信区间排 除了一个重要效果，而且基线风险低。 9. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[91], [85], [89], [83], [92], [88], [90], [86]。 10. 偏倚风险：严重。2 项试验（491 名患者；占总数的 3%）的偏倚风险低，而 6 项试验（14910 名患者）的偏倚风险高。 不精确性：严重。GDG一致认为可信区间包含一些对过敏反应的担忧，尽管也承认基线风险低。 11. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[89]。 12. 不精确性：非常严重。 13. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[93], [88], [94], [95], [96], [92], [89]。 14. 偏倚风险：严重。除了一项研究之外，所有其他研究都没有采取足够的盲法。不精确性：严重。可信区间没有排除小而 重要的益处。 15. 系统综述.基线/对照组：干预组的参考对照组。支持性参考文献：[92], [88], [90]。 16. 偏倚风险：严重。几乎所有患者都被随机分配至非盲试验。不精确性：严重。可信区间没有排除重要益处。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 63 of 119 6.9.1 作用机制 提出的恢复期血浆疗法的主要作用机制是将之前感染后康复的患者的血浆中的内生中和抗体转移至活动性感染患者体内(97)。 因此，这种作用机制的潜在合理性取决于经过从供血者到受血者的稀释后是否仍具有足够的抗体浓度。这样一来，供血者血浆中 的中和抗体滴度以及输注体积就可能很重要。叙利亚金黄地鼠产生的数据表明，输注1毫升体积的恢复期血浆在1:2560的滴度下对 SARS-CoV-2有效，但在1:320的滴度下无效，这是根据人体输注300毫升剂量后的平均血容量推断得出的(98)。 在对恢复期血浆进行临床研究并报告了中和抗体滴度和输注体积的研究中，极端情况下，输注200毫升预计会导致平均稀释25 倍，而输注1000毫升预计产生的稀释是供血者自身循环中存在的滴度的平均5倍的稀释（假设平均5升的人血容量(99)）。应该进一 步认识到，不同供血者的恢复期血浆中存在的中和抗体的浓度（滴度）差异很大，并且滴度测定的方法也有多种(100)。 在关于此COVID-19疗法的所有研究中，抗体滴度、所用的方法和输注的恢复期血浆体积都有很大差异。还应进一步指出，在 一些试验中，报告的合格血浆的抗体滴度高于所用供血者血浆中报告的抗体滴度，这是因为两次抗体滴度测定采用了不同的方法 （例如，对供血者合格性评估采用总IgG（免疫球蛋白G）法并随后评估特异性中和抗体滴度(101))。围绕着各个试验中输注的中 和抗体剂量存在着明显的不确定性，总结如下： 对重症/危重症患者的试验： • 在 16研究中的 9项研究里，没有设定供血者中和抗体滴度的临界值。 • 在 16 研究中的 12 项研究里，没有记录供血者血浆的抗体滴度，这意味着滴度可能高也可能低。然而，在 3 项没有记录 供血者滴度的试验中，设定了较低的临界值，分别为 1:160（2项试验）和 1:400的滴度。 • 最大的一项试验（“康复”）没有报告供血者的抗体滴度，尽管只有滴度超过 1:100的供血者才有资格参加试验。 • 一项（16项中的 1项）试验没有提供输注的血浆体积信息，这意味着体积可能高也可能低。 • 在 16研究中仅有 6项研究既提供了输注体积也提供了供血者滴度的数据。供血者滴度分别为 1:80、1:87、1:300、1:320、 1:526和 1:640，输注体积分别为 300、500、400–600、约 480、750-975以及 300毫升（估计的剂量范围为 6倍）。 对非重症患者的试验： • 仅在非重症患者中进行了三项试验，使用了 1:40、1:292和 1:3200的抗体滴度，输注体积分别为 250-300毫升、400毫升 和 250毫升（估计的剂量范围为 100倍）。 • 两项试验既研究了非重症患者，也研究了重症/危重症患者，其中一项试验没有记录抗体滴度，另一项使用了滴度为 1:160的 200–250+/-75毫升的血浆。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 64 of 119 6.10. 卡西瑞单抗-伊德维单抗（中和单克隆抗体）（2021年9月24日发布） 信息栏 2021年9月24日，关于对COVID-19非重症、重症或危重症患者使用中和单克隆抗体（卡西瑞单抗-伊德维单抗）进行治疗的 建议作为世卫组织动态指南的第六版发布，并在《英国医学杂志》上作为快速建议发表。指南在四个试验发布的预印本后制 定，这四个试验是针对非重症患者的更大的适应性随机化主方案的一部分，也是针对重症和危重症患者的“康复”试验的一部 分(9)(10)(11)。 在先前发表了对卡西瑞单抗-伊德维单抗的有条件建议后，出现了更多的临床前证据（见“作用机制”）(102）。有大量的 临床前体外数据，以及确定的体内评估，表明卡西瑞单抗-伊德维单抗对奥密克戎BA.1变异株缺乏疗效（见“作用机制”）。 因此，不再建议将卡西瑞单抗-伊德维单抗用于COVID-19的治疗，除非有快速的病毒基因分型并确认感染了易受这一单克隆抗 体组合中和活性影响的SARS-CoV-2变异株（如德尔塔）。 GDG指出，对于住院风险最高的COVID-19非重症患者，有几种替代治疗方案（见第6.1节和建议下的备注）。 在本第十一版的指南中，对恢复期血浆的建议没有做出任何修订。 用于住院风险最高的COVID-19非重症患者 有条件建议 更新 我们建议对病毒基因分型可确认为易受此疗法影响的SARS-CoV-2变异株（即除外奥密克戎BA.1）的患者使用卡西瑞单抗-伊 德维单抗进行治疗。（有条件建议） • 关于识别最高住院风险患者的帮助，参阅第 6.1 节。 • 有几种治疗方案可供选择：参见决策支持工具，该工具列出了奈玛特韦-利托那韦、莫努匹拉韦、瑞德西韦和单克隆抗 体（包括索托维单抗和卡西瑞单抗-伊德维单抗）的利弊。 • GDG 得出结论，奈玛特韦-利托那韦可能是一种更优的选择，因为它在预防住院方面可能比替代药物具有更大的疗效， 关于其危害的关切少于莫努匹拉韦；并且比静脉输注瑞德西韦和抗体更易于给药。 实用信息 剂量和给药途径：各项非重症患者试验中进行单克隆抗体联合用药时使用的静脉总剂量有所不同，从总剂量1200毫克到8000 毫克（每种抗体各600毫克到各4000毫克）不等，证明了在所有剂量下药物都有效，包括最低的试验总剂量1200毫克（每种抗体各 600毫克）。考虑到有限的获取途径和资源，卫生系统将面临关于卡西瑞单抗-伊德维单抗的剂量选择以及采用静脉注射还是皮下 注射的选择。请参见（“决策证据”中）“可接受性和可行性”部分的考量因素，以帮助在1200毫克至2400毫克的总剂量范围内 做出选择。 监测：尽管现有试验没有令人信服地表明卡西瑞单抗-伊德维单抗会导致过敏反应，但这种可能性仍然存在。通过置管内灭菌 或连接0.2微米过滤器的方式进行静脉置管给药。给药后，应监测患者是否会出现严重过敏反应。 决策证据 利弊 在非重症患者中，卡西瑞单抗-伊德维单抗很可能会降低住院风险和症状持续时间。卡西瑞单抗-伊德维单抗不太可能有严重的 不良反应，包括过敏反应。 证据的确定性 现有的以实证为依据开发的确定患者住院风险的风险预测工具存在局限性，这是导致GDG下调证据确定性等级的间接性的主 要来源(31)。此外，GDG认为，由于可能出现一些导致药效降低的变异株，也存在一些间接性。因此，GDG将需住院治疗和症状 持续时间的证据确定性下调为中等。由于不精确性的存在，GDG将过敏反应的证据确定性下调为中等，但认为没有严重不良反应 的结论属于高确定性证据。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 65 of 119 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG推断，几乎所有完全知情的、典型的低住院风险患者都会拒绝使用卡西瑞单 抗-伊德维单抗，只有风险较高的患者（如未接种疫苗、老年人或免疫抑制的患者）会选择这种治疗。 资源和其他考虑因素 可接受性和可行性 GDG指出，所有愿意选择接受此疗法的人不太可能都能够获得卡西瑞单抗-伊德维单抗。这进一步支持了卡西瑞单抗-伊德维 单抗应留给住院风险最高患者的指导意见。 影响可行性的主要因素包括卡西瑞单抗-伊德维单抗的产量有限，以及对门诊患者来说需要静脉给药的要求。关于静脉注射， 可能需要配备有足够数量的抗体药物和人员的专门诊所进行操作，以确保安全有效地给药。要想大量使用这种干预措施，卫生系 统必须解决这些挑战。 选择剂量：在不同的试验中使用了不同剂量的单克隆抗体组合，卫生系统将面临使用哪种剂量的选择，这可以通过价值观和 偏好来决定。如果首要任务是让尽可能多的人有机会从治疗中获益，那么可以使用非重症患者研究中采用的最低有效剂量，即 1200毫克总剂量（每种抗体各600毫克）(103)。如果首要任务是确保对每个接受治疗的个体患者有效，并最大限度地降低产生耐药 性的风险，那么可以使用更高的2400毫克（每种抗体各1200毫克）的静脉给药总剂量。 给药途径：在静脉给药和皮下给药之间进行选择时会出现类似的价值观和偏好问题，LNMA中纳入的（属于更大的适应性随 机化主方案下的）四项试验使用的是静脉给药(104)，而预防性试验使用的是皮下给药(105)。静脉给药比皮下给药更快达到最大药 物浓度；然而，两者都会达到高于提出的治疗阈值的暴露量。如果首要任务是确保每个接受治疗的个体患者获得最大效果，那么 可能会选择静脉注射。如果在社区广泛操作静脉注射具有实际困难，而首要任务是让尽可能多的人有机会从此治疗方法中受益， 那么可能会使用皮下注射作为替代性给药途径。皮下给药仅限于最低剂量，即总剂量为1200毫克（每种抗体各600毫克）。 理由 证据、价值观和偏好以及可行性结合起来促成有条件建议仅在住院风险最高的COVID-19非重症患者中使用卡西瑞单抗-伊德 维单抗。尽管有中等确定性证据表明可大幅降低住院的相对风险，但只有少数属于风险最高的患者才有可能获得重要益处。在对 COVID-19非重症患者的常规治疗中，缺乏可靠的工具来识别住院风险最高的患者。这种临床复杂性，加上药物的可得性有限，以 及需要对通常在社区治疗的患者采取不经肠道的给药方式，给治疗带来了一系列挑战，需要卫生保健系统来解决。 适用性 本建议对儿童的适用性目前尚不确定，因为纳入的随机对照试验仅招募了成人。GDG没有理由认为患有COVID-19的儿童对卡 西瑞单抗-伊德维单抗的治疗会有任何不同的反应。然而，儿童住院的风险通常极低，因此GDG推断，除非存在免疫抑制或其他重 大风险因素，不应对儿童使用此干预措施。 临床问题/PICO 对象：COVID-19非重症患者 干预：卡西瑞单抗-伊德维单抗 对照：标准治疗 摘要 证据摘要 对于COVID-19非重症患者，LNMA(2)汇总了四项试验的数据，共招募了4722名随机分配到卡西瑞单抗-伊德维单抗或常规 护理的患者(104)。GDG审查数据时，所有试验均已登记，并发布了预印本。此表显示了试验特征。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，卡西瑞单抗-伊德维单抗与常规治疗 相比对COVID-19非重症患者的相对效果和绝对效果，并给出了证据确定性评级。 关于为绝对效果估计值提供依据的基线风险估计值的特定考虑因素 对于住院这一促使建议使用卡西瑞单抗-伊德维单抗的关键结局，基于形成证据的四个随机对照试验的对照组的中位数，我 们使用了4.2% (42/1000)的基线风险值。这些试验招募了住院风险较高的患者，以提高发现潜在治疗效果的统计能力。因此，基 线风险明显高于许多COVID-19非重症患者的风险。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 66 of 119 亚组分析 没有证据表明对COVID-19非重症患者存在按年龄或发病时间的亚组效应。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 使用卡西瑞单抗- 伊德维单抗 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比：0.57 （95%置信区间 0.26 - 1.2） 基于 4项研究中 4722名患者的数据 （随机对照） 6 每 1000人 3 每 1000人 中等 因严重的间接性 1 卡西瑞单抗和 伊德维单抗对死亡率 不产生重要效果。 差异：每 1000 人减少 3 例 （95%置信区间减少 4例-增加 1例） 机械通气 优势比：0.22 （95%置信区间 0.03 - 1.21） 基于 2项研究中 3432名患者的数据 （随机对照） 8 每 1000人 2 每 1000人 中等 因严重的间接性 2 卡西瑞单抗和 伊德维单抗很可能 对机械通气没有 重要影响。 差异：每 1000 人减少 6 例 （95%置信区间减少 8例-增加 2例） 住院 试验中风险 优势比：0.29 （95%置信区间 0.17 - 0.48） 基于 4项研究中 4722名参与者的数据 （随机对照） 35 每 1000人 10 每 1000人 中等 因严重的间接性 3 卡西瑞单抗和 伊德维单抗很可能 会减少住院。 差异：每 1000 人减少 29 例 （95%置信区间减少 29例-减少 18例） 住院 较高风险 优势比：0.29 (95%置信区间 0.17 - 0.48） 基于 4项研究中 4722名参与者的数据 （随机对照） 60 每 1000人 18 每 1000人 中等 因严重的间接性 4 卡西瑞单抗和 伊德维单抗很可能 会减少住院。 差异：每 1000 人减少 42 例 （95%置信区间减少 49例-减少 30例） 住院 最高风险 优势比：0.29 (95%置信区间 0.17 - 0.48） 基于 4项研究中 4722名参与者的数据 （随机对照） 100 每 1000人 31 每 1000人 中等 因严重的间接性 5 卡西瑞单抗和 伊德维单抗很可能 会减少住院。 差异：每 1000 人减少 69 例 （95%置信区间减少 81例-减少 49例） 导致停药的 不良反应 基于 4项研究中 5284名参与者的数据 （随机对照） 0 每 1000人 95%置信区间 高 卡西瑞单抗- 伊德维单抗很可能 不会造成导致停药的 不良反应的 显著增加。 差异：每 1000 人减少 8 例 （95%置信区间） 过敏反应 基于 4项研究中 15406名参与者的数据 （随机对照） 3 每 1000人 9 每 1000人 中等 因严重的不精确性 6 卡西瑞单抗和 伊德维单抗很可能 不会造成过敏反应的 显著增加。 差异：每 1000 人增加 6 例 （95%置信区间减少 1例-增加 29例） 症状消除 所需时间 越低越好 基于 2项研究中 3084名参与者的数据 9 （均值） 4.9 （均值） 中等 因严重的间接性 5 卡西瑞单抗和 伊德维单抗很可能 会缩短症状改善的 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 67 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 使用卡西瑞单抗- 伊德维单抗 证据的确定性 （证据质量） 纯文本摘要 （随机对照） 差异：平均差减少 4.1 （95%置信区间减少 5.7–减少 1.8） 时间。 住院时长 （基线时未住院） 越低越好 基于 2项研究中 111名患者的数据 （随机对照） 9.6 （均值） 8.2 （均值） 低 因非常严重的 不精确性 6 卡西瑞单抗- 伊德维单抗对住院 时长可能没有 重要影响。 差异：平均差减少 1.4 （95%置信区间减少 4.6–增加 1.8） 1. 间接性：严重。不同患者之间的基线死亡风险差异很大。卡西瑞单抗-伊德维单抗可能对死亡风险较高的患者有重要益 处。 2. 间接性：严重。不同患者之间的机械通气的基线风险差异很大。卡西瑞单抗-伊德维单抗可能对机械通气风险较高的患者 有重要益处。 3. 间接性：严重。关注群体和研究群体之间存在差异：目前传播的主要变异株与研究期间传播的变异株不同。 4. 间接性：严重。关注群体和研究群体之间存在差异：目前传播的主要变异株与研究期间传播的变异株不同。 5. 间接性：严重。关注群体和研究群体之间存在差异：目前传播的主要变异株与研究期间传播的变异株不同。 6. 不精确性：严重。 7. 间接性：严重。目标群体和研究群体之间存在差异：目前传播的主要变异株与研究期间传播的变异株不同。 8. 不精确性：非常严重。 用于COVID-19重症或危重症患者 有条件建议使用 更新 我们建议对血清阴性状态、且病毒基因分型可确认为对该疗法易感的SARS-CoV-2变异株（即除外奥密克戎BA.1）的患 者，使用卡西瑞单抗-伊德维单抗进行治疗。（有条件建议） • 鉴于卡西瑞单抗-伊德维单抗的益处仅在血清阴性患者中观察到，临床医生需要通过卫生服务点可获得的可信检测来 识别这些患者，才能够适当应用本建议（参见“决策证据”部分）。 • 卡西瑞单抗-伊德维单抗的治疗是对当前标准治疗的补充，标准治疗包括使用皮质类固醇和白介素-6 受体阻滞剂。 实用信息 剂量和给药途径：在招募了COVID-19重症和危重症患者的“康复”试验中，单克隆抗体组合的静脉给药总剂量为8000毫克 （每种抗体各4000毫克），而在（更大的适应性随机化主方案下的）非重症患者的四项试验中，剂量从静脉注射总剂量1200毫克 到8000毫克不等。考虑到有限的获取途径和资源，卫生系统将面临关于卡西瑞单抗-伊德维单抗的剂量选择。请参见（“决策证 据”中）“可接受性和可行性”部分的考量因素，以帮助在2400毫克至8000毫克的总剂量范围内做出选择。 诊断性检测：当患者出现COVID-19重症或危重症迹象时，需要进行具有足够性能特征的快速血清学检测以识别血清阴性患 者。如“可接受性和可行性”部分中所述，卫生保健系统需要实施此类检测。 监测：尽管现有试验没有令人信服地表明卡西瑞单抗-伊德维单抗会导致过敏反应，但这种可能性仍然存在。通过置管内灭菌 或连接0.2微米过滤器的方式进行静脉置管给药。注射后，应监测患者是否会出现过敏反应。 决策证据 利弊 在COVID-19重症和危重症患者的总群体中，卡西瑞单抗-伊德维单抗对死亡率可能没有影响，对机械通气和住院时长的影响 非常不确定。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 68 of 119 一项可信的亚组效应表明，卡西瑞单抗-伊德维单抗很可能会降低血清阴性患者的死亡率，绝对效果为重症患者每1000人中减 少39例死亡（95%置信区间：减少62例–减少13例），危重症患者为每1000人中减少69例死亡（95%置信区间：减少110例–减少23 例）。在血清阴性患者中，此干预措施可能会减少对机械通气的需要（绝对效果估计值为每1000人中减少42例；95%置信区间： 减少74例–减少6例）。除了基于血清学状态的可信亚组效应外，我们没有发现非重症患者中存在基于患者年龄或发病时间的亚组 效应证据，也没有发现重症和危重症患者中存在基于年龄、发病时间和疾病严重程度的亚组效应证据。 证据的确定性 在COVID-19重症和危重症患者中，死亡率证据的确定性低，这是由于不精确性以及卡西瑞单抗-伊德维单抗在整组中对血清 阴性和血清阳性患者很可能有非常不同的效果。在这个群体中，还由于对偏倚风险的担忧，此干预措施对机械通气需要和住院时 长的影响的证据确定性评为非常低。 对于血清阴性的COVID-19重症和危重症患者，由于担心不精确性（置信区间包括一些如1000人中14例的小影响，患者可能认 为不重要）和间接性（可能出现导致卡西瑞单抗-伊德维单抗抗体的效果降低的变异株），死亡率证据被评为中等。对于机械通 气，GDG指出，由于缺乏盲法而产生的偏倚风险也令人担忧，导致证据的确定性评为低。对于住院时长，GDG也发现了非常严重 的不精确性，导致证据的确定性很低。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG推断，绝大多数完全知情的、血清阴性的COVID-19重症或危重症患者都会 选择接受卡西瑞单抗-伊德维单抗治疗。其他患者（血清阳性或血清状态不确定的患者）可能会拒绝使用此干预措施。 尽管GDG侧重于个体患者的角度，但他们也考虑了群体的角度，其中可行性、可接受性、公平和成本是重要的考虑因素。在 本疗法中，可行性考虑在有条件建议中发挥了重要作用。对于重症和危重症患者，此疗法的有限可得性和需要进行血清学检测以 识别血清阴性患者才能作出临床决策的考虑也很重要。 资源和其他考虑因素 成本和可得性 考虑到卡西瑞单抗-伊德维单抗的成本和可得性，以及与血清学检测相关的挑战，低收入和中等收入国家获得这些药物的困难 可能非常大。因此，小组关于让血清阴性患者接受此干预措施的建议可能会加剧卫生不公平。另一方面，鉴于已证明对患者的益 处，这些建议应激励调动所有可能的机制参与改善全球获得此干预措施的机会。各国可根据可用资源制定自己的指南，并相应地 确定治疗方案的优先次序。 可接受性和可行性 卡西瑞单抗-伊德维单抗的供应可能有限，这造成了可获得性的问题，并可能带来配给方面的挑战。此外，要想获益于此疗 法，需要在患者出现重症和危重症迹象时识别其血清学状态。因此，快速准确的血清学检测以及药物的剂量和给药途径是卫生保 健系统需要考虑的关键因素。 快速血清学检测：现在已有可能负担得起的、性能特征与“康复”试验中用于表征血清阴性患者的参考标准检测方法（即牛 津针对抗SARS-CoV-2刺突蛋白的血清IgG进行的基于荧光的酶联免疫吸附试验（ELISA））类似的检测方法，通过一组阳性对照 品人为地确定临界值。一些侧向流动检测方法可能也适用，通常可以在几分钟内完成(106)(107)(108)。然而，卫生保健系统必须具 备选择和实施检测或快速检测方面的专业知识，从而选择最适合其环境的检测方法。 剂量选择：针对重症和危重症患者的临床试验（“康复”）测试了使用总剂量8000mg（每种抗体各4000 mg）的卡西瑞单抗- 伊德维单抗；针对非重症患者的临床试验使用了1200mg–8000mg（各600mg–4000mg）的总剂量，这些剂量在减少住院必要性方面 的效果基本相同。总剂量为1200mg–8000mg（每种单克隆抗体各600mg–4000mg）时卡西瑞单抗-伊德维单抗在COVID-19非重症患 者中的药代动力学特征可得(104)。这一研究表明，即使在总剂量为最低的1200毫克（每种抗体各600毫克）时，也能在血清中迅速 达到目标治疗浓度并维持28天，尽管注意到个体患者之间的药物血清浓度有很大差异。因此，使用低于“康复”试验中使用的剂 量（总剂量为8000毫克）治疗重症和危重症患者也可能会获得相同的效果。但另一方面，可能重症和危重症患者的药代动力学与 非重症患者不同，会导致药物暴露量的降低，这在理论上是成立的，但未经测试（见“作用机制”）。这将增加某些个体患者的 药物暴露量达不到最优的风险，进而增加治疗失败和产生病毒耐药性的风险。 在没有使用低于8000毫克的剂量治疗重症和危重症患者的临床数据的情况下，剂量选择可以根据价值观和偏好来决定。如果 首要任务是确保对每个接受治疗的个体都有效，并最大限度地降低产生耐药性的风险，那么可以使用8000毫克（每种抗体各 4000mg）的静脉注射总剂量。如果药物供应有限且费用高昂，而首要任务是让尽可能多的人有机会从治疗中获益，那么可以使用 低至2400毫克（每种抗体各1200mg）的静脉注射总剂量。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 69 of 119 在药物短缺的时候，可能有必要通过临床分诊对卡西瑞单抗-伊德维单抗的使用进行优先排序。一种可能性是优先考虑基线死 亡风险最高的患者（如危重症患者优先于重症患者），因为他们获得的治疗的绝对益处最大。例如，尽管卡西瑞单抗-伊德维单抗 在血清阴性患者中的相对效果是一致的（死亡率的优势比为0.85），但在危重症患者中的死亡率绝对风险降低程度为每1000人死 亡减少69例（95%置信区间：死亡减少110例至减少23例），而在重症患者中的降低程度为每1000人死亡减少39例（95%置信区 间：死亡减少62例至减少13例）。 其他缺乏直接证据的优先排序建议包括，侧重于临床病程持续恶化的患者，以及在已确诊为多器官衰竭的患者中避免使用卡 西瑞单抗-伊德维单抗治疗（这些患者的获益可能较小）。 理由 在重症或危重症患者中，有条件建议使用卡西瑞单抗-伊德维单抗反映了治疗获益可能仅限于血清阴性患者的情况。在提供重 症和危重症患者所有证据的“康复”试验中，基线的血清学状态是在预先计划的回顾性分析中进行评估的，使用了实验室抗刺突 蛋白检测。为了将试验结果转化为临床实践，在实施治疗前，需要将血清学状态评估纳入临床决策路径。这意味着在出现重症或 危重症病情时要快速识别血清学状态，以指导在该人群中的使用。 现在有几种快速、相对便宜且具有足够的性能特征的检测方法，在可获得卡西瑞单抗-伊德维单抗治疗患者的情况下，这些检 测方法应得到越来越多的应用。 适用性 所纳入的随机对照试验都没有招募儿童，因此本建议对儿童的适用性目前尚不确定。幸运的是，儿童患有COVID-19危重症的 情况极少。对于血清阴性的危重症儿童患者，他们也可能会受益于卡西瑞单抗-伊德维单抗。由于缺乏数据，GDG无法为其他特殊 人群（如孕妇）专门提出建议。 临床问题/PICO 对象： COVID-19重症或危重症患者，血清阴性 干预： 卡西瑞单抗-伊德维单抗 对照： 标准治疗 摘要 证据摘要 LNMA参考了一项针对重症和危重症患者的大型试验（“康复”），该试验招募了9785名患者，其中大多数接受了皮质类 固醇治疗(109)。在GDG进行数据审查时，该试验已经登记并发布了预印本。此表显示了试验特性。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，卡西瑞单抗-伊德维单抗与常规治疗 相比对血清阴性的COVID-19重症和危重症患者的相对效果和绝对效果，并给出了证据确定性评级。 关于为绝对效果估计值提供依据的基线风险估计值的特定考虑因素 对于COVID-19重症和危重症患者的死亡率这一关键结局，应用的基线风险估计值为13%（130/1000）。本指南中的其他相 关建议的估计值来自针对重症和危重症患者的“团结”试验，并根据皮质类固醇的治疗效果进行了调整。 为了计算血清阴性患者死亡率的基线风险估计值，我们认为“康复”试验的对照组为最佳来源。对于血清阴性状态的患 者，其重症（26%；260/1000）和危重症（46%；460/1000）的死亡风险显著高于总人群。因此，血清阴性患者是非常高风险的 人群，尽管相对风险只降低了15%，但死亡率的绝对风险大幅降低（重症患者为3.9%，危重患者为6.9%）。 亚组分析 一个高度可信的亚组效应表明，卡西瑞单抗-伊德维单抗可能会降低血清阴性患者的死亡率，但不会降低血清阳性患者的死 亡率。 使用ICEMAN工具评估了亚组效应的可信度[110]。亚组效应的可信度得到了以下因素有力的支持：一个具有特定方向的先 验假设；少量这样的假设；基于研究内比较的证据；机械通气中显示出了类似的亚组效应；以及交互作用的p值为0.001。 图2为血清阳性和血清阴性患者中关于死亡率效果的点估计值和置信区间的森林图，证明了对血清阴性患者的益处，显示 了对血清阳性患者的危害，并且置信区间没有重叠，这一结果与交互作用检验中的p = 0.001相对应(109)。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 70 of 119 图 2. 血清阳性和血清阴性的 COVID-19重症和危重症患者的死亡率 CI：置信区间，RR：相对危险度。 很低确定性的证据显示了能够缩短血清阴性患者住院时间的可能性。除了报告的基于血清学状态的亚组效应，我们没有发 现基于年龄、发病时间和严重程度（比较重症和危重症患者）的亚组效应证据。 结局 时限 研究结果和衡量标准 对照组 不使用卡西瑞单抗和 伊德维单抗 干预组 使用卡西瑞单抗和 伊德维单抗 证据的确定性 （证据质量） 纯文本摘要 死亡率 重症 相对危险度：0.85 （95%置信区间 0.76 - 0.95） 基于 1项研究中 2823名参与者的数据 （随机对照） 260 每 1000人 221 每 1000人 中等 因对不精确性和 间接性的担忧 1 卡西瑞单抗- 伊德维单抗很可能 会降低死亡率。 差异：每 1000 人减少 39 例 （95%置信区间减少 62例-减少 13例） 死亡率 危重症 相对危险度：0.85 （95%置信区间 0.76 - 0.95） 基于 1项研究中 2823名参与者的数据 （随机对照） 460 每 1000人 391 每 1000人 中等 因对不精确性和 间接性的担忧 2 卡西瑞单抗- 伊德维单抗很可能 会降低死亡率。 差异：每 1000 人减少 69 例 （95%置信区间减少 110例-减少 23例） 机械通气 相对危险度：0.87 （95%置信区间 0.77 - 0.98） 基于 1项研究中 2410名参与者的数据 （随机对照） 320 每 1000人 278 每 1000人 低 因对偏倚风险、 不精确性和间接性的 担忧 3 卡西瑞单抗- 伊德维单抗可能 会减少机械通气。 差异：每 1000 人减少 42 例 （95%置信区间减少 74例-减少 6例） 住院时长 基于 1项研究中 3153名参与者的数据 （随机对照） 使用卡西瑞单抗-伊德维单抗后住院时间 中位数缩短了 4天（13天相对于 17天） 非常低 因对严重的偏倚 风险、严重的间接性 和非常严重的 不精确性的担忧 4 对住院时长的影响 非常不确定。 1. 不精确性：严重。单个研究。 2. 不精确性：严重。单个研究。 3. 偏倚风险：严重。不精确性：严重。 4. 偏倚风险：严重。间接性：严重。不精确性：非常严重。 结局，亚组 REGEN-COV 常规治疗 相对危险度 (95% CI) 0.91) 血清阴性 396/1633 (24%) 0.98 (0.78–1.22) 全部参与者 944/4839 (20%) 0.94 (0.86–1.03) 28天内死亡 451/1520 (30%) 1026/4946 (21%) 未知 血清阳性 1.09 (0.95–1.26) 0.80 (0.70–0.91) 383/2636 (15%) 192/790 (24%) 411/2636 (16%) 137/570 (24%) 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 71 of 119 临床问题/PICO 对象： COVID-19重症和危重症患者 干预： 卡西瑞单抗-伊德维单抗 对照： 标准治疗 摘要 证据摘要 网络荟萃分析的证据摘要来自一项针对重症和危重症患者的大型试验（“康复”），该试验招募了9785名患者，其中大多 数接受了皮质类固醇治疗(109)。在GDG对数据进行审查时，该试验已登记并发布了预印本。此表显示了试验特征。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，卡西瑞单抗-伊德维单抗与常规治疗 相比对COVID-19重症和危重症患者的相对效果和绝对效果，并给出了证据确定性评级。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 使用卡西瑞单抗和 伊德维单抗 证据的确定性 （证据质量） 纯文本摘要 死亡率 危重症或重症 优势比：0.94 （95%置信区间 0.86 - 1.03） 基于 1项研究中 9785名参与者的数据 （随机对照） 130 每 1000人 122 每 1000人 低 因严重的间接性和 不精确性 1 卡西瑞单抗-伊德维 单抗对死亡率可能 没有重要影响。 差异：每 1000 人减少 8 例 （95%置信区间减少 18例-增加 4例） 机械通气 优势比：0.95 （95%置信区间 0.87 - 1.04） 基于 1项研究中 6637名参与者的数据 （随机对照） 86 每 1000人 82 每 1000人 很低 因严重的偏倚风险、 间接性和不精确性 2 对机械通气的影响 非常不确定。 差异：每 1000 人减少 4 例 （95%置信区间减少 11例-增加 3例） 过敏反应 基于 4项研究中 15406名参与者的数据 （随机对照） 3 每 1000人 9 每 1000人 中等 因严重的不精确性 3 卡西瑞单抗- 伊德维单抗很可能 不会导致过敏反应的 显著增加。 差异：每 1000 人增加 6 例 （95%置信区间减少 1例-增加 29例） 导致停药的 不良反应 基于 4项研究中 5284名参与者的数据 （随机对照） 2 每 1000人 1 每 1000人 高 卡西瑞单抗- 伊德维单抗不会造成 导致停药的不良 反应的显著增加。 差异：每 1000 人减少 1 例 （95%置信区间增加 0例-增加 1例） 住院时长 基于 1项研究中 9785名参与者的数据 （随机对照） 两组患者的住院时长 中位数相同（10天） 很低 因严重的偏倚风险 和非常严重的 不精确性 4 对住院时长的影响 非常不确定。 1. 间接性：严重。不精确性：严重。 2. 偏倚风险：严重。间接性：严重。不精确性：严重。 3. 不精确性：严重。 4. 偏倚风险：严重。不精确性：非常严重。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 72 of 119 6.10.1 作用机制 卡西瑞单抗-伊德维单抗是两种完全人源化的抗体（REGN10933和REGN10987）。其作用机制看上去非常合理：它们与SARS- CoV-2刺突蛋白结合(111)，并在恒河猴和叙利亚金黄地鼠中显示出了抗病毒活性(112）。COVID-19非重症患者的药代动力学数据 显示，在联合用药静脉注射总剂量为1200毫克（每种抗体各600毫克）或以上后，两种抗体均达到了抗病毒浓度并维持了至少28天 (42)。在未感染的个体中，使用1200毫克总剂量（每种抗体各600毫克）的皮下注射进行预防，也可以达到并维持抗病毒浓度 (105)。两种抗体的半衰期为25天到37天。目前尚无卡西瑞单抗-伊德维单抗在COVID-19重症和危重症患者中的药代动力学数据， 但这些数据很重要，因为曾报告过其他单克隆抗体的血清浓度在发生全身炎症期间较低，并与白蛋白和C反应蛋白水平相关 (113)。现有数据还表明，当联合用药时，针对目前流行的需要关注的变异株的活性仍然存在(114)。 虽然其作用机制看上去合理，但据推测，与没有产生抗SARS-CoV-2刺突蛋白抗体（以下简称血清阴性）的患者相比，对于自 己产生抗SARS-CoV-2刺突蛋白抗体（以下简称血清阳性）的患者，给药效果可能会有不同。推测认为治疗效果可能在尚未产生有 效抗体反应的血清阴性个体中更大或仅限于这些患者。 描述单克隆抗体对不同变异株体外中和作用的数据被整理在美国国立卫生研究院国家推进转化科学中心（NIH NCATS）的开 放数据门户中（https://opendata.ncats.nih.gov/variant/activity）。若干报告表明，当分开研究卡西瑞单抗-伊德维单抗时，它们对含有 BA.1奥密克戎刺突蛋白的假病毒以及BA.1奥密克戎真病毒的体外中和作用会急剧减少或消失，而当两种单克隆抗体联合使用时则 完全消失。此外，卡西瑞单抗-伊德维单抗的组合对感染BA.1奥密克戎的K18人类ACE2转基因小鼠的肺部或鼻甲中的亚基因组病毒 核糖核酸没有影响（https://www.biorxiv.org/content/10.1101/2022.01.23.477397v1.full.pdf+html）。因此，目前现有的临床前数据不 支持卡西瑞单抗和伊德维单抗组合对BA.1 奥密克戎变异株的活性。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 73 of 119 6.11. 白介素-6 受体阻滞剂（2021 年 7 月 6 日发布） 信息栏 2021年7月6日，关于白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）的建议作为世卫组织动态指南的第五版发布，并在 《英国医学杂志》作为快速建议发布。在此之前，“康复”和REMAP-CAP试验出版物于2021年2月发表，世卫组织于2021年6 月1日获得关于REMAP-CAP中被头对头随机分配到托珠单抗或沙利鲁单抗的1020名患者的新试验数据。本第十一版指南没有就 关于白介素-6受体阻滞剂的建议作出修改。 世卫组织强烈建议在COVID-19重症和危重症患者中使用JAK抑制剂，特别是巴瑞替尼。白介素-6受体阻滞剂和巴瑞替尼不 应该同时给药，而应被视为替代药物。关于白介素-6受体阻滞剂的建议中的“理由”部分陈述了这些新的考虑因素，在本第十 一版指南中没有变更。 用于COVID-19的重症或危重症患者 强烈建议使用 我们建议使用白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）治疗。（强烈建议使用） • 皮质类固醇之前曾被强烈建议用于COVID-19重症和危重症患者的治疗(见第6.15节)，我们建议符合这些严重程度标准 的患者现在应该同时接受皮质类固醇和白介素-6受体阻滞剂治疗。 • 巴瑞替尼是一种JAK抑制剂，现在被建议用于治疗COVID-19重症和危重症患者（见第6.7节）。白介素-6受体阻滞剂 和巴瑞替尼不应同时给药，而应被视为替代药物。选择使用巴瑞替尼还是白介素-6受体阻滞剂，取决于可获得性以及 临床和环境因素（见“理由”）。 实用信息 途径：对COVID-19重症和危重症患者给予静脉注射白介素-6受体阻滞剂治疗；在这种情况下不使用皮下给药。白介素-6受体 阻滞剂治疗应与全身性皮质类固醇联合使用，皮质类固醇可口服和静脉给药，并要适当考虑到虽然其生物利用度高，但在危重症 伴肠道功能障碍的情况下可能出现吸收不良。 疗程：托珠单抗和沙利鲁单抗采用单次静脉给药，通常超过1小时。第二剂可在第一剂后12至48小时给药；在主要临床试验中 如果主治的临床医生认为临床反应不充分，会酌情提供第二剂。同时进行的全身性皮质类固醇的给药持续时间通常为10天，但可 能在5至14天之间不等。 剂量：托珠单抗的剂量为每千克实际体重8毫克，最高可达800毫克。沙利鲁单抗最常见的剂量为400毫克，与REMAP-CAP试 验中使用的剂量一致。这两种药物目前都不需要根据肾功能调整剂量。 监测：在开始治疗前，应检查血常规，包括中性粒细胞计数、血小板、转氨酶和总胆红素。鉴于除全身性皮质类固醇外还会 进一步增加免疫抑制的风险，应监测所有患者的感染体征和症状。接受更长期白介素-6受体阻滞剂治疗的患者有活动性结核病、 侵袭性真菌感染和机会性病原体感染的风险。对于除COVID-19以外还有任何其他活动性、严重感染的患者，应仔细权衡治疗的风 险和益处；在考虑给有复发或慢性感染史患者或有潜在感染倾向的基础疾病患者使用托珠单抗时，建议保持谨慎。 用药时机：白介素-6受体阻滞剂应与全身性皮质类固醇一起开始使用；没有具体说明在住院期间或病程中何时使用。虽然如 此，在被纳入的试验中，白介素-6受体阻滞剂是在住院早期进行给药的，如有可能，临床医生可考虑这种做法。见对资源的影 响、公平和人权一节。 决策证据 利弊 高确定性证据表明，白介素-6受体阻滞剂可降低死亡率和对机械通气的需要。低确定性证据表明，白介素-6受体阻滞剂也可能 降低机械通气和住院的时间(3)(115)(116)。 关于严重不良事件风险（SAEs）的证据尚不确定。低确定性证据表明，在用白介素-6受体阻滞剂进行免疫抑制治疗的情况 下，细菌感染的风险可能与常规治疗相似(1)。然而，GDG有一些担忧，鉴于大多数试验的随访期较短以及难以准确发现细菌或真 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 74 of 119 菌感染的不良事件，证据摘要可能低估了使用白介素-6受体阻滞剂治疗的风险。此外，作为建议依据的白介素-6受体阻滞剂试验大 多在高收入国家进行，这些国家的某些感染并发症的风险可能低于世界上其他地方，因此尚不清楚其不良事件数据是否具有普遍 性。我们没有收到研究白介素-6受体阻滞剂单剂或双剂治疗的危害风险差异的数据。 亚组分析表明，疗效没有根据白介素-6受体阻滞剂药物（沙利鲁单抗或托珠单抗）或疾病严重程度（危重症对比重症）的不 同而有变化，因此本建议适用于所有COVID-19重症或危重症的成年患者(110)。由于试验数据不足，我们无法按炎症标志物的升高 水平或不同年龄开展亚组分析（见“研究证据”）。评价基线类固醇使用的亚组分析发现，接受类固醇治疗的患者比未接受类固 醇治疗的患者从白介素-6受体阻滞剂获得的受益更大(p=0.026)，表明类固醇的使用不会消除却还可能增强白介素-6受体阻滞剂的有 益效果。由于类固醇已经被强烈建议用于COVID-19重症或危重症患者，我们没有正式评价该亚组分析的可信度，因为没有理由为 未接受皮质类固醇治疗的患者提供亚组建议。 证据的确定性 死亡率和机械通气需要的证据被评为高确定性证据。机械通气持续时间的证据被评为低确定性证据，因为考虑到被纳入的试 验中缺乏盲法会导致严重的偏倚风险，并且置信区间的下限表明无效果而导致不精确。住院持续时间的证据被评为低确定性证 据，这是因为被纳入的试验缺乏盲法而存在严重的偏倚风险，而且由于点估计值差异和置信区间缺乏重叠而导致存在不一致性。 严重不良事件的证据被评为很低确定性证据，因为存在缺乏盲法和确认偏倚导致的偏倚风险，并且由于非常宽的置信区间没 有排除重大的利或弊而导致的非常严重的不精确性；细菌或真菌感染风险的证据被评为低确定性证据，原因也是对严重的偏倚风 险和严重的不精确性的担忧。 由于不精确性的问题，在比较托珠单抗和沙利鲁单抗对死亡率的影响时，证据的确定性被评为中等。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG大多数成员推断，几乎所有完全知情的患者都希望接受白介素-6受体阻滞剂 治疗。白介素-6受体阻滞剂对降低死亡率的益处被认为对患者至关重要，尽管严重不良事件的证据确定性很低。GDG预计不同患 者之间对这种干预措施的价值观和偏好鲜有差异。 资源和其他考虑因素 对资源的影响、公平和人权 GDG指出，与COVID-19的一些其他候选疗法相比，白介素-6受体阻滞剂更昂贵，且本建议并没有考虑成本效益问题。目前， 在世界许多地方获得此类药物都比较困难，而且如果没有协调一致的努力，这种情况可能会持续下去，特别是在资源匮乏的地 区。因此，强烈建议使用白介素-6受体阻滞剂就可能会加剧卫生不公平。另一方面，鉴于对患者的明显益处，此建议还应刺激人 们采用所有可能的机制以提高此疗法在全球的可得性。各国可根据可用资源制定自己的指南，并相应地对治疗方案进行优先排 序。 在药物短缺时，可能有必要通过临床分诊确定哪些人可以优先使用白介素-6受体阻滞剂进行治疗(6)。许多辖区都提出了对这 些治疗方法进行分诊后使用的机制。其中包括优先考虑基线死亡风险最高的患者（例如危重症患者的优先性高于重症患者），因 为这样的治疗绝对收益最大。例如，尽管白介素-6受体阻滞剂的相对效果是一致的（死亡率优势比0.86），但在降低危重症患者死 亡率的绝对风险方面为每1000人减少31例死亡（95%置信区间：减少11至47例死亡），而对重症患者死亡率的影响为每1000人减 少13例死亡（95%置信区间：减少5至19例死亡）。 其他优先排序的建议（缺乏直接证据）包括侧重于临床病程持续恶化的患者，以及避免对已确诊的多器官衰竭患者（受益可 能较小）使用白介素-6受体阻滞剂治疗。 可接受性和可行性 由于白介素-6受体阻滞剂需要静脉给药，这种治疗主要适用于需要住院治疗的COVID-19重症和危重症患者。白介素-6受体阻 滞剂给药相对容易，只需要一剂，或最多两剂。 理由 当根据证据强烈建议给COVID-19重症或危重症患者使用白介素-6受体阻滞剂（托珠单抗或沙利鲁单抗）时，GDG强调了提高 生存率和降低机械通气需要方面的高确定性证据。来自REMAP-CAP的额外试验数据（见“研究证据”部分）提供了关于托珠单 抗和沙利鲁单抗等效性的更确凿的证据。 GDG承认关于严重不良事件和细菌感染的数据缺乏确定性，但认为在两个最重要的患者结局上的有益证据值得强烈建议使用 这一疗法。费用和药物的获取是重要的考虑因素，同时也认识到这项建议可能会加剧卫生不公平。希望这一强烈建议将会推动解 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 75 of 119 决这些担忧，并确保各个区域和国家都能获得药物。GDG认为患者的价值观和偏好不会有重要差异，并断定其他背景因素不会改 变本建议（见“决策证据”）。 亚组分析 GDG没有发现任何证据表明不同疾病严重程度（重症对比危重症）的患者之间或不同白介素-6受体阻滞剂（托珠单抗对比沙 利鲁单抗）之间存在亚组效应。 没有足够的数据可以按炎症标记物的水平或年龄来进行亚组效应评估。尽管GDG审议了对基线时接受皮质类固醇治疗的患者 与未接受皮质类固醇治疗的患者进行比较的亚组分析，但小组认为没有必要为未接受皮质类固醇治疗的患者制定白介素-6受体阻 滞剂的亚组建议，因为所有COVID-19重症和危重症患者都应接受皮质类固醇治疗（见下文中之前做出的强烈建议）。综上所述， GDG认为本建议适用于托珠单抗和沙利鲁单抗以及所有COVID-19重症和危重症的成年患者。 白介素-6 受体阻滞剂和巴瑞替尼的相互关系 世界卫生组织最近强烈建议巴瑞替尼用于COVID-19重症和危重症患者。这两类药物都是免疫调节剂，对免疫反应的影响有重 叠。因此，一种合理的可能性是，它们对COVID-19的影响不会是叠加的。此外，在同时给药时，包括继发性细菌或真菌感染在内 的不良反应有可能会增大。在没有证据表明这些药物同时给药会带来增量效益的情况下，GDG建议临床医生不要同时给药。 参见JAK抑制剂的“理由”部分和相关的研究结论汇总表（见研究证据），以了解有关选择疗法的更为详细的讨论。 适用性 被纳入的随机对照试验都没有招募儿童，因此本建议对儿童的适用性目前尚不确定。然而，GDG没有理由认为患有COVID-19 的儿童对白介素-6受体阻滞剂的治疗会有任何不同的反应。托珠单抗尤其如此，因为它已经在儿童中安全地用于其他适应症，包 括多关节幼年类风湿性关节炎、幼年慢性关节炎的全身发作和嵌合抗原受体T细胞诱导的细胞因子释放综合征。沙利鲁单抗没有被 批准用于儿童，因此，如果在儿童中使用白介素-6受体阻滞剂，则首选托珠单抗。GDG还认识到，在许多情况下，儿童往往因其 他病原体引起的急性呼吸道疾病而住院；因此，即使有阳性检测结果，也难以辨别哪些儿童是COVID-19重症患者并因此可能受益 于白介素-6受体阻断。对于孕妇也有类似的考虑，虽然没有直接研究孕妇的数据，但没有理由表明她们会与其他成年人有不同的 用药反应。然而，这种药物可能会穿过胎盘膜，尽管暂时的免疫抑制对胎儿有什么影响尚不确定，但应把这种情况与对母亲的潜 在益处放在一起权衡考虑。 临床问题/PICO 对象： COVID-19重症和危重症患者 干预： 巴瑞替尼 对照： 白细胞介素-6受体阻滞剂 结局 时限 研究结果和衡量标准 对照组 白介素-6受体阻滞剂 干预组 巴瑞替尼 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比0.77 (95%置信区间 0.53-1.1) 基于3项研究的 2659名参与者数据。 （随机对照） 118 每1000人 96 每1000人 低 因严重的不精确性和 大型随机对照试验的 持续招募1 巴瑞替尼可能降低 死亡率。 差异：每1000人减少22例 （95%置信区间减少52例 — 增加9例） 机械通气 优势比1.01 (95%置信区间 0.61-1.6) 基于2项研究的 2434名参与者数据。 （随机对照） 94 每1000人 96 每1000人 低 因非常严重的 不精确性2 机械通气方面可能 几乎没有差异。 差异：每1000人增加2例 （95%置信区间减少38例 — 增加44 例） 导致停药的 不良反应 基于4项研究的 2309名参与者数据。 （随机对照） 0 每1000人 1 每1000人 中等 因严重的不精确性 3 导致停药的不良 反应方面很可能 几乎没有差异。 差异：每1000人增加1例 （95%置信区间减少11例 — 增加15 例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 76 of 119 住院时长 越低越好 基于3项研究的 2652名参与者数据。 （随机对照） 8.1 天（中位数） 11.2 天（中位数） 很低 因严重的偏倚风险， 严重的不一致性， 和非常严重的 不精确性4 对住院时长的影响 非常不确定。 差异：平均差增加3.1天 （95%置信区间减少3.8天 — 增加9.9天） 机械通气时长 越低越好 基于2项研究的 328名参与者数据。 （随机对照） 13.8 天（中位数） 11.6 天（中位数） 低 因严重的偏倚风险和 不精确性5 巴瑞替尼可能降低 机械通气时长。 差异：平均差减少2.2天 （95%置信区间减少5.3天 — 减少0.7天） 临床稳定 所需时间 越低越好 基于2项研究的 2558名参与者数据。 （随机对照） 8.4 天（中位数） 8.9 天（中位数） 低 因严重的偏倚风险和 不精确性6 在临床稳定所需 时间方面可能没有 重要影响。 差异：平均差增加0.5天 （95%置信区间减少2.3例 — 增加3.2 例） 1. 不精确性：严重。可信区间内无重要差异。 2. 偏倚风险：不严重。关于白细胞介素-6 受体阻滞剂的大部分数据来自非盲法的试验。不精确性：非常严重。可信区间包 括重要益处和重要危害。 3. 不精确性：严重。可信区间包括小但重要的危害。 4. 偏倚风险：严重。大多数关于白细胞介素-6受体阻滞剂的数据来自于非盲法的试验。不一致性：严重。研究白细胞介素- 6 受体阻滞剂的试验结果不一致：有些增加了住院时间，有些减少了住院时间。不精确性：非常严重。可信区间包括重 要益处和重要危害。 5. 偏倚风险：严重。关于白细胞介素-6 受体阻滞剂的大部分数据来自于非盲法的试验。不精确性：严重。可信区间内无重 要差异。 6. 偏倚风险：严重。白细胞介素-6 受体阻滞剂的大部分数据来自非盲法的试验。不精确性：严重。可信区间包括重要损害 和重要益处（使用的最小重要差异阈值为 1天）。 临床问题/PICO 对象： COVID-19重症和危重症患者 干预： 白细胞介素-6受体阻滞剂 对照： 标准治疗 摘要 证据摘要 关于白介素-6受体阻滞剂的LNMA(8)参考了10618名参与者参加的30个随机对照试验，提供了除死亡率（来自前瞻性荟萃分 析(PMA)(116)）以外的所有对患者重要的结局的相对效果估计值。LNMA纳入的所有试验都进行了登记，研究对象为COVID-19 重症和危重症患者（可申请提供试验特征表）。在这些试验中，37%发表在同行评议的期刊上，3%可提供预印本，60%已完成 但未发表。 死亡率的证据摘要基于对来自27个随机对照试验的10930名参与者的前瞻性荟萃分析(116)。我们对死亡率使用前瞻性荟萃 分析数据是因为它额外包含了一些未发表的死亡结局报告数据。GDG认识到，不同中心和地区的常规治疗可能存在差异，且在 不断变化中。然而，鉴于所有数据均来自随机对照试验，在被随机分配到干预组或常规治疗组的参与者之间，对这些构成常规 治疗的联合干预措施的使用应该是平衡的。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，白介素-6受体阻滞剂与常规治疗相比 的对COVID-19重症和危重症患者的相对效果和绝对效果，并给出了确定性评级。关于绝对效果估计值参考的基线风险估计值 来源，参见第7节。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 77 of 119 亚组分析 所有被纳入的随机对照试验仅评估了需要住院治疗的COVID-19重症和危重症成年患者使用白介素-6受体阻滞剂的情况。 GDG要求按年龄（不足70岁对比老年患者）、疾病严重程度（重症对比危重症）、炎症标记物水平和基线皮质类固醇使用情况 对以下结局进行亚组分析：死亡率、机械通气的需求和时长、住院时长以及严重不良事件和细菌感染的风险。 根据亚组分析，GDG认定，对于所有预设的人们关注的结局，不存在基于疾病严重程度的亚组效应。GDG审议了一项对所 有被纳入的随机对照试验基于全身皮质类固醇的使用情况进行亚组分析的结果。该分析表明，白介素-6受体阻滞剂的相对效果 依全身皮质类固醇的基线使用而异。最为重要的是，类固醇并没有消除甚至可能增强白介素-6受体阻滞剂对死亡率的有益效 果。出于下述原因，GDG没有正式评估该亚组分析的可信度。 当根据前瞻性荟萃分析比较托珠单抗和沙利鲁单抗时，没有证据表明存在亚组效应(116)。然而，托珠单抗+类固醇对比单 用类固醇的数据（优势比0.77，95%置信区间0.68–0.87）比沙利鲁单抗+类固醇对比单用类固醇的数据（优势比0.92，95%置信 区间0.61–1.38）更多，因而精确度也更高。除了这些亚组数据之外，GDG还审查了REMAP-CAP研究人员提供的头对头数据， 这些数据表明，在所有接受皮质类固醇治疗的患者中，托珠单抗与沙利鲁单抗的效果没有差异（使用托珠单抗的死亡率为 36.5%，使用沙利鲁单抗的死亡率为33.9%）。比较托珠单抗+类固醇和沙利鲁单抗+类固醇效果的网络荟萃分析估计值结合了直 接和间接数据，提供了两种药物无差别的中等确定性数据（优势比1.07，95%置信区间0.86–1.34）(1)(3)。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 白介素-6阻滞剂 证据的确定性 （证据质量） 纯文本摘要 死亡率（重症和 危重症患者） 优势比：0.86 (95%置信区间 0.79-0.95) 基于 27项研究中 10930名患者的数据 1 （随机对照） 130 每 1000人 114 每 1000人 高 白介素-6抑制剂 能降低死亡率。 差异：每1000人减少16例 （95%置信区间减少 24例-减少 6例） 机械通气 优势比：0.72 (95%置信区间 0.57–0.9) 基于 9项研究中 5686名患者的数据 2 （随机对照） 86 每 1000人 63 每 1000人 高 白介素-6抑制剂 能减少对机械 通气的需要。 差异：每1000人减少23例 （95%置信区间减少 35例-减少 8例） 导致停药的 不良事件 优势比：0.5 (95%置信区间 0.03–9.08) 基于 2项研究中 815名患者的数据 3 （随机对照） 9 每 1000人 5 每 1000人 很低 因严重的偏倚风险 和非常严重的 不精确性 4 白介素-6受体阻滞剂 对导致停药的不良 事件的影响不确定。 差异：每1000人减少4例 （95%置信区间增加 0例-增加 67例） 细菌感染 优势比：0.95 (95%置信区间 0.72–1.29) 基于 18项研究中 3548名患者的数据 （随机对照） 101 每 1000人 96 每 1000人 低 因严重的偏倚风险和 严重的不精确性 5 白介素-6受体阻滞剂 可能不会增加继发性 细菌感染。 差异：每1000人减少5例 （95%置信区间减少 26例-增加 26例） 机械通气持续 时间 越低越好 基于 10项研究中 1189名患者的数据 （随机对照） 14.7 (均值) 13.5 (均值) 低 因严重的偏倚风险和 严重的不精确性 6 白介素-6受体阻滞剂 可能会缩短机械 通气的持续时间。 差异：平均差减少1.2 （95%置信区间减少 2.3-减少 0.1） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 78 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 白介素-6阻滞剂 证据的确定性 （证据质量） 纯文本摘要 住院持续时间 越低越好 基于 9项研究中 6665名 患者的数据 （随机对照） 12.8 (均值) 8.3 (均值) 低 因严重的偏倚风险和 严重的不一致性 7 白介素-6受体阻滞剂 可能会缩短住院 时间。 差异：平均差减少4.5 （95%置信区间减少6.7-减少2.3） 1. 基线/对照组：主要研究[15]。死亡率和机械通气的基线风险来自世卫组织针对 COVID-19 重症和危重症患者的“团结” 试验，对作为标准治疗一部分的皮质类固醇进行了调整（16%基线风险 x 皮质类固醇相对危险度 0.79=13%）。世卫组织 “团结”试验的对照组遍布多个国家和地域，被GDG认定为 COVID-19重症和危重症患者死亡率和机械通气基线风险估 计值的最相关的证据来源。 2. 系统综述[3]。基线/对照组：主要研究。死亡率和机械通气的基线风险来自世卫组织针对 COVID-19 重症和危重症患者 的“团结”试验，对作为标准治疗一部分的皮质类固醇进行了调整（16%基线风险 x 皮质类固醇相对危险度 0.79=13%）。世卫组织“团结”试验的对照组遍布多个国家和地域，被 GDG 认定为 COVID-19 重症和危重症患者死亡 率和机械通气基线风险估计值的最相关的证据来源。 3. 系统综述。基线/对照组：干预组的参考对照组。我们使用了被纳入的研究中的所有随机分配到常规治疗的患者的中位 事件率。支持性参考文献：[3]。 4. 偏倚风险：严重。由于对缺乏盲法和确认偏倚的偏倚风险的一些担忧，我们进行了降级。不精确性：非常严重。我们进 行降级是因为置信区间非常宽跨 0了。 5. 偏倚风险：严重。由于对缺乏盲法和确认偏倚的偏倚风险的一些担忧，我们进行了降级。不精确性：严重。降级是因为 置信区间非常宽跨 0了。 6. 偏倚风险：严重。由于对缺乏盲法的偏倚风险的一些担忧，我们进行了降级。不精确性：严重。我们进行降级是因为置 信区间的下限接近 0。 7. 偏倚风险：严重。由于对缺乏盲法的偏倚风险的一些担忧，我们进行了降级。不一致性：严重。降级是因为点估计值的 差异以及置信区间缺乏重叠。 6.11.1 作用机制 白介素-6是一种多效性细胞因子，可激活和调节对感染的免疫反应。白介素-6浓度升高与COVID-19重症的结局相关，包括呼 吸衰竭和死亡，尽管白介素-6在此病发病机理中的作用尚不清楚。 托珠单抗和沙利鲁单抗是批准用于治疗类风湿性关节炎的单克隆抗体，是白介素-6的膜结合和可溶性受体（IL-6R/sIL-6R）的 拮抗剂。托珠单抗被批准以静脉给药的方式治疗类风湿性关节炎，而沙利鲁单抗被批准采用皮下给药的方式，虽然在COVID-19研 究中这两种药物都采取了静脉给药的方式。在COVID-19的研究剂量下，这两种药物都有望达到基于类风湿性关节炎研究的非常高 的受体占有率(29)。这里仅改变了白介素-6受体阻滞剂的适应症，并没有改变其主要的药理作用机制。其疗效取决于白介素-6信号 传导在COVID-19病理生理学中的重要性，而不取决于所用剂量是否达到了目标浓度。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 79 of 119 6.12. 伊维菌素（2021年 3月 31日发布） 信息栏 2021年3月31日，关于伊维菌素的建议作为世卫组织动态指南的第四版发布，并在《英国医学杂志》上作为快速建议发 表。此前，伊维菌素作为一种潜在的治疗选项受到了越来越多的国际关注。在本第十一版指南中，未对关于伊维菌素的建议做 出任何修订。 自我们提出建议以来，我们注意到一些新的、相对较小的试验已经发表，并且出于对研究欺诈的担忧，一项关键的试验已 经被撤回(117)(118)。然而，来自LNMA的最新证据摘要与我们之前提出的建议相一致。GDG将在本指南的后续迭代中对更新的 证据摘要进行充分审议。 用于COVID-19患者（无论疾病严重程度） 仅在研究环境中使用 除非在临床试验中，否则我们建议不使用伊维菌素（仅在研究环境中建议使用）。 备注：本建议适用于任何疾病严重程度和任何症状持续时间的患者。 当证据确定性很低，并且未来的研究在降低干预措施效果的不确定性和以合理的成本进行干预方面有很大的潜力时，建议 仅在临床试验中使用该药物是合适的。 实用信息 GDG建议不要在临床试验环境之外使用伊维菌素治疗COVID-19患者，因此实践方面的考虑因素与此药的关联性不大。 决策证据 利弊 伊维菌素对死亡率、机械通气、入院、住院时间和病毒清除的效果仍然不确定，因为关于这些结局的证据确定性很低。伊维 菌素可能对临床改善时间影响很小或没有影响（低确定性证据）。伊维菌素可能会增加导致停药的严重不良事件风险（低确定性 证据）。 亚组分析表明没有基于剂量的效果改变。由于试验数据不足（见研究证据），我们无法按患者年龄或疾病严重程度进行亚组 分析。因此，我们假设所有亚组的效果都很相似。本建议适用于任何疾病严重程度和任何症状持续时间的患者。 证据的确定性 对于大多数关键结局，包括死亡率、机械通气、入院、住院时间和病毒清除，GDG认为证据的确定性很低。证据被评定为确 定性很低的主要原因是大多数结局的证据的不精确性非常严重：汇总数据的置信区间很宽和/或含有的事件很少。还对一些结局的 偏倚风险非常担忧，特别是缺乏盲法，缺乏试验预登记，以及一项试验没有报告机械通气的结局，尽管在他们试验方案中预先进 行了指定（发表性偏倚）。 更多详细信息，请参见本条建议中的“理由”部分。对于其他结局，包括严重不良事件和临床改善时间，证据的确定性评为 低。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG推断，鉴于证据在对死亡率、机械通气需要、住院需要和其他关键结局的 效果方面有非常高的不确定性，并且存在危害的可能性，例如与治疗相关的严重不良事件，几乎所有完全知情的患者都希望仅在 随机试验的情况下才会接受伊维菌素治疗。小组预计不同的患者对这种干预措施的价值观和偏好没有什么差异。 资源和其他考虑因素 伊维菌素是一种相对便宜的药物，可广泛获得，包括在低收入环境中。GDG认为，在药物的益处非常不确定，并且其危害仍 然令人担忧的情况下，低成本和广泛的可得性并不意味着必须要使用这种药物。尽管患者的平均成本可能较低，但GDG提出了担 忧，即这会使关注点和资源离开可能带来益处的治疗（如对COVID-19重症患者的皮质类固醇治疗和其他支持性治疗干预措施）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 80 of 119 此外，使用伊维菌素治疗COVID-19会使该药的供应偏离其明确的适应症，有可能导致药物短缺，特别会对蠕虫控制和消除规划有 影响。还应考虑使用皮质类固醇可能会导致病情恶化的其他地方性传染病。如果在COVID-19治疗中使用类固醇，也许仍可考虑在 类圆线虫病流行的地区使用伊维菌素进行经验性治疗，虽然这不是对COVID-19本身的治疗，应由主治临床医生酌情决定。 理由 当根据证据提出建议仅在临床试验背景下对COVID-19患者使用伊维菌素时，GDG强调了在最关键的结局上证据的高度不确定 性，如死亡率和机械通气需要。小组还指出，证据表明治疗可能会带来危害，导致不良事件的增加。GDG预计患者们的价值观和 偏好不会有什么重大差异。其他背景因素（如资源考虑、可获得性、可行性和对卫生公平的影响）没有改变这项建议。 与之前世卫组织《疗法与2019冠状病毒病（COVID-19）：动态指南》所评估的药物相比，目前可得的伊维菌素随机对照试验 的数据少之又少。伊维菌素的现有数据的不确定性也高出很多，被纳入的试验所招募的患者少得多，事件也少得多。 高度不确定性 伊维菌素在包括死亡率在内的主要相关结局上的效果估计值的确定性很低，因此伊维菌素对这些结局的效果仍属不确定。不 确定性主要有两个来源：严重的偏倚风险；和严重的不精确性。尽管构成该药的证据摘要依据的随机对照试验有16项，但只有5项 直接将伊维菌素与标准治疗进行了对比并报告了死亡率 (119)(120)(121)(122)(123)(124)(125)。值得注意的是，根据我们一贯使用的 方法，LNMA团队排除了准随机试验和任何没有使用明确随机技术的随机对照试验。在这五个随机对照试验中，有两个(119)(120) 由于盲法不充分而存在高偏倚风险。这两项试验中的一项(119)还在试验方案公布之前开始招募和随机分配患者，这也是导致偏倚 风险增加的因素。基于试验偏倚风险进行的死亡率亚组分析说明了偏倚风险的潜在影响。如森林图（图3）所示，直接比较伊维菌 素和标准治疗的所有五个随机对照试验的集合估计值表明伊维菌素降低了死亡率，但如果我们只考虑偏倚风险低的试验（这些试 验加起来贡献了近三分之二的证据），这种效果并不明显。这一发现增加了伊维菌素对死亡率影响的真实效果的不确定性。与直 接证据一致，将伊维菌素与标准治疗（通过与羟氯喹和洛匹那韦/利托那韦进行比较）进行比较的间接证据也观察到了类似的现 象。表明伊维菌素降低死亡率的间接证据几乎全部来自一项研究，而该研究由于缺乏对盲法或随机化的详细描述以及缺乏可公开 获得的研究方案（图未显示）而存在高偏倚风险(117)。 图 3. 显示伊维菌素与标准治疗对死亡率的影响的直接对比森林图，带有按偏倚风险分组的亚组分析 IV：逆方差。 除去与偏倚风险相关的担忧之外，还对死亡率的结局的不精确性存在非常严重的担忧。根据GRADE的要求，不精确性要根据 置信区间方法和信息样本量（事件数量）的评价来进行评估，以确保有足够的信息来做出明智的判断(126)。在这种情况下，尽管 置信区间方法表明伊维菌素有益处，但信息样本量很低。就死亡率而言（并忽略上述与偏倚风险相关的担忧），随机分配到伊维 菌素组的511名患者中有9人死亡（1.76%），随机分配到标准治疗组的404名患者中有22人死亡（5.45%）。如果作为结论基础，那 么这个事件量极少，远远低于最优信息样本量。事实上，从理论上来说，只要将三个事件（死亡）从随机分到标准治疗组更改为 随机分到伊维菌素组，就消除了任何统计学意义，这一发现表明，完全可以合理地把结果仅归因于偶然性。此外，这一比较所依 据的证据来自多个小型试验，增加了研究组别中存在着未被认识到的不平衡性的风险。鉴于偶然性很可能在观察到的结论中发挥 作用，小组认为存在非常严重的不精确性，从而进一步降低了结论的总体确定性。 研究或亚组 伊维菌素 事件 总数 标准治疗 事件 总数 权重 风险率 IV，固定，95%置信区间 高偏倚风险 低偏倚风险 风险率 IV， 固定， 95% 置信区间 0.01 1000.1 1 10 支持[伊维菌素] 支持[标准治疗] Kirti 0 55 4 57 6.30% 0.12 [0.01, 2.09] Niaee 4 120 11 60 43.90% 0.18 [0.06, 0.55] 小计（95%置信区间） 175 117 50.30% 0.17 [0.06, 0.48] 事件总数 4 15 Gonzalez 5 36 6 37 44.50% 0.86 [0.29, 2.56] Lopez 0 200 1 198 5.20% 0.33 [0.01, 8.05] Mohan 0 100 0 52 Not estimable 小计（95%置信区间） 336 287 49.70% 0.77 [0.28, 2.18] 事件总数 5 7 总计（95%置信区间） 511 404 100% 0.36 [0.17, 0.75] 事件总数 9 22 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 81 of 119 尽管点估计值和置信区间似乎表明伊维菌素有益处，但是严重的偏倚风险再加上非常严重的不精确性导致死亡率证据的确定 性很低。因此，小组得出结论，伊维菌素对死亡率的影响尚不确定。对其他关键结局也有类似的考虑，包括机械通气、入院和住 院时间，并导致这些结局的证据确定性也很低。 亚组分析 我们只按伊维菌素的剂量进行了效果的亚组分析，小组没有发现任何亚组效应的证据（见研究证据）。缺乏试验内部的比较 使得无法按年龄或疾病严重程度进行亚组分析。因此，小组没有对此药提出任何亚组建议。换言之，除临床试验外不使用伊维菌 素的建议适用于所有疾病严重程度、年龄组和伊维菌素的所有剂量方案。 适用性 被纳入的随机对照试验都没有招募15岁以下的儿童，因此该建议对儿童的适用性目前尚不确定。然而，小组没有理由认为患 有COVID-19的儿童对伊维菌素的治疗会有不同的反应。对孕妇也有类似的考虑，没有数据直接研究孕妇群体，但没有理由表明她 们会有和其他成年人不同的用药反应。 临床问题/PICO 对象： COVID-19感染患者（所有疾病严重程度） 干预： 伊维菌素 对照： 标准治疗 摘要 证据摘要 证据摘要基于16项随机对照试验和2407名参与者。在被纳入的研究中，75%研究了非重症患者，25%研究了重症和非重症 患者。许多被纳入的研究没有就我们关注的结局进行报告。在这些研究中，25%发表在同行评议的期刊上，44%发布了预印 本，31%已完成但未发表（见此表的试验特征）。我们还排除了一些准随机对照试验(127)(128)(129)(130)。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，伊维菌素与常规治疗相比对COVID- 19患者的相对效果和绝对效果，并给出了证据确定性评级。请参见第7节获取作为绝对效果估计值依据的基线风险估计值来 源。 亚组分析 网络荟萃分析团队进行了亚组分析，以针对不同亚组制定不同建议。从现有数据来看，亚组分析只能按伊维菌素的剂量进 行，并考虑了死亡率、机械通气、入院和导致停药的不良事件等结局。按伊维菌素剂量进行的亚组分析直接比较伊维菌素和常 规治疗。在这些分析中，使用元回归来评价作为连续变量的累积剂量的效果，还进一步增加了一个用于评价单剂对比多剂给药 方案的协变量。这种方法基于药理学专家（由Andrew Owen教授领导）的意见，他们对各种试验剂量进行了药代动力学模拟， 发现当把单剂量和多剂量研究分开时，伊维菌素的累积剂量预计与关键药代动力学参数相关。需要指出的是，被纳入的试验并 未直接评估伊维菌素的药代动力学，我们的方法以模拟为基础，并尽可能对照已公布的人体药代动力学信息对模拟进行验证。 小组使用预先指定的框架，结合ICEMAN工具来评估亚组研究结果的可信度(110)。 GDG请求根据以下因素进行亚组分析：年龄（儿童对比年轻人对比老年人[70岁或以上]组）；疾病严重程度（COVID-19非 重症对比重症对比危重症）；症状出现的时间；以及联合用药的情况。然而，根据我们预先指定的方案，试验内部的数据不足 以进行这些亚组分析。小组认识到，不同中心和地区的常规治疗也可能存在差异，而且常规治疗也在不断变化中。然而，鉴于 所有数据均来自随机对照试验，在随机分配到干预组或常规治疗组的研究患者之间，对这些构成常规治疗的联合干预措施的使 用应该是平衡的。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 82 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 伊维菌素 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比：0.19 （95%置信区间 0.09–0.36） 基于 7项研究中 1419名 参与者的数据 1。 （随机对照） 70 每 1000人 14 每 1000人 非常低 由于严重的偏倚 风险和非常严重的 不精确性 2 伊维菌素对死亡率的 影响尚不确定。 差异：每 1000人减少 56例 （95%置信区间减少 63例-减少 44例） 机械通气 优势比：0.51 (95%置信区间 0.12–1.77) 基于 5项研究中 687名 参与者的数据。 （随机对照） 20 每 1000人 10 每 1000人 非常低 由于非常严重的 不精确性和 发表性偏倚 3 伊维菌素对机械 通气的影响 尚不确定。 差异：每 1000 人减少 10 例 （95%置信区间减少 18例-增加 15例） 病毒清除 7天 优势比：1.62 （95%置信区间 0.95–2.86） 基于 6项研究中 625名 参与者的数据。 （随机对照） 500 每 1000人 618 每 1000人 低 由于严重的 不一致性和 不精确性 4 伊维菌素可能会改善 病毒清除或 不产生影响。 差异：每 1000 人增加 118 例 （95%置信区间减少 13例-增加 241例） 入院 （仅门诊患者） 优势比：0.36 （95%置信区间 0.08–1.48） 基于 1项研究中 398名 参与者的数据。 （随机对照） 50 每 1000人 18 每 1000人 非常低 由于极为严重的 不精确性 5 伊维菌素对入院的 影响尚不确定。 差异：每 1000 人减少 32 例 （95%置信区间减少 47例-增加 23例） 严重不良事件 优势比：3.07 （95%置信区间 0.77–12.09 基于 3项研究中 584名参与者的数据。 （随机对照） 9 每 1000人 27 每 1000人 低 由于非常严重的 不精确性 6 伊维菌素可能会增加 导致停药的严重不良 事件的风险。 差异：每 1000 人增加 18 例 （95%置信区间增加0例-增加89例） 临床改善时间 度量单位：天数 越低越好 基于 2项研究中 633名 参与者的数据。 （随机对照） 11 天（均值） 10.5 天（均值） 低 由于非常严重的 不精确性 7 伊维菌素可能对临床 改善的时间影响很小 或没有影响。 差异：平均差减少 0.5 天 （95%置信区间减少 1.7天-增加 1.1天） 住院时间 度量单位：天数 越低越好 基于 3项研究中 252名 参与者的数据。 （随机对照） 12.8 天（均值） 11.7 天（均值） 非常低 由于严重的 不精确性、 不一致性和严重的 偏倚风险 8 伊维菌素对住院时间 的影响尚不确定。 差异：平均差减少 1.1 （95%置信区间减少 2.3天-增加 0.1天） 病毒清除时间 度量单位：天数 越低越好 基于 4项研究中 559名参与者的数据 （随机对照） 7.3 天（均值） 5.7 天（均值） 非常低 由于非常严重的 不精确性和严重的 偏倚风险 9 我们不确定伊维菌素 是改善还是恶化了 病毒清除时间。 差异：平均差减少 1.6 天 （95%置信区间减少 4.1天-增加 3天） 1. 系统综述[1]。基线/对照组：干预组的参考对照组。我们选择使用世卫组织“团结”试验的对照组，反映了全部参与试 验的国家的常规治疗。 2. 偏倚风险：严重。贡献大部分效果估计值的大型试验是由非盲研究。不精确性：非常严重。事件总数很少。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 83 of 119 3. 不精确性：非常严重。事件很少并且可信区间包括重要利弊。发表性偏倚：严重。 4. 不一致性：严重。点估计值差异很大，可信区间没有大幅重叠。不精确性：严重。可信区间不包含任何效果。 5. 不精确性：极为严重。可信区间包括重要利弊。 6. 不精确性：非常严重。可信区间包括很少或根本不包括差异。 7. 不精确性：非常严重。 8. 偏倚风险：严重。结果来自一项非盲法研究；不一致性：严重。尽管置信区间有重叠，点估计值还是不一致。不精确 性：严重。可信区间没有包括差异。 9. 偏倚风险：严重。对偏倚风险的担忧。不精确性：非常严重。可信区间包括重要利弊。 6.12.1 作用机制 伊维菌素是一种抗寄生虫药，通过结合谷氨酸门控氯离子通道干扰蠕虫的神经和肌肉功能(131)。基于体外实验，一些人推测 伊维菌素可能对SARS-CoV-2有直接的抗病毒作用。然而，提出的治疗COVID-19的剂量在人体内不太可能达到体外抑制所需的浓 度(132)(133)(134)。在叙利亚金黄地鼠SARS-CoV-2感染模型中，伊维菌素对SARS-CoV-2的病毒RNA没有影响(135)。提出的机制 仍然不明确：已经提出的多个靶标要么是基于与生命周期非常不同的其他病毒的类比，要么是像数百个其他候选药一样，基于与 包括刺突、RdRp和3CLpro在内的多个病毒靶标进行分子对接的模拟(136)(137)(138)(139)(140)。目前没有直接证据支持任何针对 SARS-CoV-2的抗病毒作用机制。 主要基于对其他适应症的研究，有人提出，伊维菌素具有免疫调节作用，但其机制仍不清楚。历史数据显示，在给予致死剂 量脂多糖的小鼠中使用伊维菌素提高了存活率(141)，并且伊维菌素在特应性皮炎和过敏性哮喘的小鼠模型中也带来益处 (142)(143)。对于SARS-CoV-2，一种假说认为免疫调节是由α-7烟碱乙酰胆碱受体的变构调节进行介导的（通过调节受体配体的活 性间接实现的）。尽管研究人员已经在体外证明了这种作用，但这些实验中使用的浓度甚至高于抗病毒效果所需的浓度(144)，因 此在人体内不太可能实现。在感染SARS-CoV-2的叙利亚金黄地鼠模型中，伊维菌素导致肺免疫表型的一些变化，这与α-7烟碱乙 酰胆碱受体的变构调节一致(135)。然而，伊维菌素似乎不能逆转体重减轻，而体重减轻是该模型中疾病的主要标志，并且没有测 量药物浓度来推断在人体中需要获得的药物浓度。总之，伊维菌素是否能产生任何免疫调节或抗炎作用仍存在很大的不确定性。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 84 of 119 6.13. 羟氯喹（2020 年 12 月 17 日发布） 信息栏 关于羟氯喹的建议于2020年12月17日作为世卫组织动态指南的第三版发布，并在《英国医学杂志》中作为快速建议发表。 此前，于2020年10月15日发布了世卫组织“团结”试验预印本，报告了在COVID-19住院患者中使用羟氯喹、瑞德西韦和洛匹 那韦/利托那韦治疗的结果(15)。在本第十一版指南中，没有对羟氯喹的建议进行修订。 用于COVID-19患者（无论疾病严重程度） 强烈建议不使用 我们建议不使用羟氯喹或氯喹。(强烈建议不使用) 备注：本建议适用于任何疾病严重程度和任何症状持续时间的患者。 实用信息 GDG强烈建议不要使用羟氯喹或氯喹治疗COVID-19患者。使用羟氯喹可能会排除使用其他也会延长QT间期的重要药物，如 阿奇霉素和氟喹诺酮类药物。应极其谨慎地合并使用延长QT间期的药物。 决策证据 利弊 羟氯喹和氯喹很可能不会降低死亡率或机械通气，也可能不会缩短住院时间。证据不排除羟氯喹导致死亡和机械通气风险小 幅增加的可能性。对其他不太重要结局的影响尚不确定，包括症状消除时间、入院和机械通气持续时间。 羟氯喹可能会增加腹泻和恶心/呕吐的风险；这一发现与在其他疾病中使用此药的证据一致。腹泻和呕吐可能会增加低血容量 症、低血压和急性肾损伤的风险，尤其是在医疗资源有限的环境中。羟氯喹是否会增加心脏毒性风险（包括危及生命的心律失 常）以及增加的程度尚不确定。 亚组分析表明，没有基于疾病严重程度（危重症对比重症/非重症或非重症对比危重症/重症）或年龄（年龄小于70岁对比老年 患者）的效果差异。此外，累积剂量和预测的第3天血清谷浓度没有改变任何结局上的效果。因此，我们假设所有亚组都有相似的 效果。 我们还审查了比较羟氯喹加阿奇霉素对比单独使用羟氯喹的证据。没有证据表明阿奇霉素的加入改变了羟氯喹对任何结局的 效果（确定性非常低）。 证据的确定性 对于死亡率和机械通气等关键结局，小组认为证据具有中等程度的确定性。还存在着对在最大的试验中缺乏盲法和不精确性 的剩余担忧。例如，集合效果的可信区间设置使得存在死亡率微小下降的可能性。腹泻和恶心/呕吐的证据质量较低，因为在许多 试验中缺乏盲法，而且报告这些结局的试验中招募的患者总数小于最优信息样本量（尽管这两种结局的可信区间完全处在危害那 一边）。 对于所有其他结局，证据的确定性评为低或非常低。数据的主要问题是不精确性（可信区间既包括重要益处也包括重要危 害）以及偏倚风险（缺乏盲法）。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），鉴于证据表明很可能对死亡率或机械通气需要没有效果，并且存在不良事件（包 括腹泻、恶心和呕吐）的风险，GDG推断，几乎所有完全知情的患者都不希望接受羟氯喹治疗。小组预计不同患者对这种干预措 施的价值观和偏好没有什么差异。 资源和其他考虑因素 和其他用于COVID-19的药物相比，羟氯喹和氯喹相对便宜，而且已经广泛可得，包括在低收入环境中。尽管如此，小组认为 几乎所有的患者都会选择不使用羟氯喹或氯喹，因为弊大于利。虽然患者的人均费用可能低，但是GDG担心这会使关注点和资源 从可能有益的治疗上（例如对COVID-19重症患者使用皮质类固醇和其他支持性治疗干预措施）转移开。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 85 of 119 理由 当根据证据提出强烈建议不要对COVID-19患者使用羟氯喹或氯喹时，小组强调有中等确定性证据表明这些药很可能不能降低 死亡率或机械通气需要。小组还指出，证据表明治疗可能会带来恶心和腹泻的弊端。GDG预见患者在价值观和偏好上无重要差 异，并认为其他背景因素（如资源考虑、可获得性、可行性和对卫生公平的影响）不会改变这项建议（见“决策证据”中对这些 因素的总结）。 亚组分析 小组没有发现任何证据表明在不同疾病严重程度、成年人和老年人之间以及不同剂量之间存在亚组效应，因此没有对此药提 出任何亚组建议。换言之，这条强烈建议适用于任何疾病严重程度、年龄组以及羟氯喹的所有剂量和剂量表。 这些试验包括了世界各地的患者，其疾病严重程度不同，并且在不同的环境下接受治疗（门诊和住院）。虽然这些试验并没有 报告按症状出现时间划分的亚组效应，但很多试验招募了处于病程早期的患者。GDG因此认为这些证据适用于所有COVID-19患者。 适用性 特殊人群 被纳入的随机对照试验没有招募过儿童，因此目前不能确定这项建议是否适用于儿童。然而，小组没有理由认为COVID-19的 儿童患者对羟氯喹的治疗会有任何不同的反应。对于孕妇也有类似的考虑，虽然没有对孕妇群体的直接研究数据，但没有理由认 为她们的用药反应会与其他成年人不同。羟氯喹可穿过胎盘屏障，存在着对其可能会导致新生儿视网膜受损的担忧。虽然羟氯喹已 用于患有全身性自身免疫疾病（如红斑性狼疮）的孕妇，但孕妇可能比其他患者有更多的理由不愿使用羟氯喹来治疗COVID-19。 与阿奇霉素联合使用 网络荟萃分析中没有证据表明联合使用阿奇霉素会改变羟氯喹对任何结局的效果。由于没有试验数据表明阿奇霉素有利于改 善羟氯喹的效果，因此不论患者是否同时接受阿奇霉素治疗，不使用羟氯喹和氯喹的建议都适用。 不确定性 剩余不确定性请参见文件结尾部分（第9节）。GDG认为未来的研究不太可能会找到一个可能受益于羟氯喹或氯喹的患者亚组。 临床问题/PICO 对象： COVID-19患者（所有疾病严重程度） 干预： 羟氯喹 对照： 标准治疗 摘要 证据摘要 羟氯喹的LNMA基于30项试验，共有10 921名参与者参加，提供了对患者重要的结局的相对效果估计值（见此表）。其中 五项试验（共有414名参与者）将一些患者随机分配到氯喹组。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，羟氯喹与常规治疗相比对COVID-19 患者的相对效果和绝对效果，并给出了证据确定性评级。请参见第7节获取作为绝对效果估计值依据的基线风险估计值来源。 亚组分析 对于羟氯喹，GDG要求按年龄（儿童对比较年轻者[如不足70岁]对比老年患者[如70岁或以上]）、疾病严重程度（非重症 对比重症对比COVID-19危重症患者）以及是否与阿奇霉素联合用药进行亚组分析。 小组还请求按高剂量对比低剂量的羟氯喹进行亚组分析。按羟氯喹剂量进行分类被证明是不可能的，因为各项试验使用了 不同的负荷剂量、持续剂量和用药持续时间。因此，我们与药理学专家（Andrew Owen教授）合作，制作了预期血清浓度随时 间而变化的模型。我们假设在治疗早期达到较高的血清谷浓度（如第3天的谷浓度）可能比较低的早期血清谷浓度更有效。我 们还假设，与较低的最大血清浓度相比，较高的最大血清浓度（例如，最后一天的峰值浓度）可能会使产生不良反应的风险更 高。在我们的药代动力学模型中，累积剂量与治疗第3天和最后一天的所有血清浓度指标的测量值高度相关，因此我们决定使 用累积剂量作为主要分析指标。第3天的谷浓度与总累积剂量的相关性最小（R2=0.376），因此我们用第3天的预期谷浓度进行 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 86 of 119 了敏感性亚组分析以了解疗效的情况。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 羟氯喹 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比：1.11 （95%置信区间 0.95-1.31） 基于 29项研究中 10859名 参与者的数据 1 （随机对照） 106 每 1000人 116 每 1000人 中等 因临界的偏倚风险 和不精确性 2 羟氯喹很可能不能 降低死亡率。 差异：每 1000 人增加 10 例 （95%置信区间减少 5例-增加 28例） 机械通气 优势比：1.2 （95%置信区间 0.83-1.81） 基于 5项研究中 6379名参与者的数据 （随机对照） 105 每 1000人 123 每 1000人 中等 因临界的偏倚风险 和严重的不精确性 3 羟氯喹很可能不能 减少机械通气。 差异：每 1000 人增加 18 例 （95%置信区间减少 16例-增加 70例） 病毒清除 7天 优势比：1.08 （95%置信区间 0.25-4.78） 基于 4项研究中 280名参与者的数据 4 （随机对照） 483 每 1000人 502 每 1000人 很低 因非常严重的 不精确性 5 羟氯喹对病毒清除的 效果非常不确定。 差异：每1000人增加19例 （95%置信区间减少 294例-增加 334 例） 入院 优势比：0.39 （95%置信区间 0.12-1.28） 基于 1项研究中 465名参与者的数据 （随机对照） 47 每 1000人 19 每 1000人 很低 因非常严重的 不精确性和严重的 间接性 6 羟氯喹对入院的影响 尚不确定。 差异：每1000人减少28例 （95%置信区间减少 41例-增加 12例） 心脏毒性 基于 7项研究中 3287名参与者的数据 （随机对照） 46 每 1000人 56 每 1000人 很低 因严重的 不精确性，偏倚 风险和间接性 7 羟氯喹对心脏毒性的 影响尚不确定。 差异：每1000人增加10例 （95%置信区间增加 0-30例） 腹泻 优势比：1.95 （95%置信区间 1.4-2.73） 基于 6项研究中 979名参与者的数据 （随机对照） 149 每 1000人 255 每 1000人 低 因严重的不精确性 和偏倚风险 8 羟氯喹可能增加 腹泻风险。 差异：每1000人增加106例 （95%置信区间增加 48-增加 174例） 恶心/呕吐 优势比：1.74 （95%置信区间 1.26-2.41） 基于 7项研究中 1429名参与者的数据 （随机对照） 99 每 1000人 161 每 1000人 低 因严重的不精确性 和严重的偏倚风险 9 羟氯喹可能增加 恶心和呕吐风险。 差异：每1000人增加62例 （95%置信区间增加 23-增加 110例） 谵妄 优势比：1.59 （95%置信区间 0.77-3.28） 基于 1项研究中 423名参与者的数据 （随机对照） 62 每 1000人 95 每 1000人 很低 因非常严重的 不精确性和严重的 间接性 10 羟氯喹对谵妄的 效果尚不确定。 差异：每1000人增加33例 （95%置信区间减少 14例-增加 116例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 87 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 羟氯喹 证据的确定性 （证据质量） 纯文本摘要 临床改善时间 越低越好 基于 5项研究中 479名参与者的数据。 （随机对照） 11 天（均值） 9 天（均值） 很低 因严重的偏倚 风险，不精确性和 间接性 11 羟氯喹对临床改善 时间的效果 尚不确定。 差异：平均差减少2天 （95%置信区间减少 4天–增加 0.1天） 住院持续时间 越低越好 基于 5项研究中 5534名参与者的数据 （随机对照） 12.8 天（均值） 12.9 天（均值） 低 因严重的不精确性 和严重的偏倚风险 12 羟氯喹可能对 住院持续时间 没有影响。 差异：平均差增加0.1天 （95%置信区间减少 1.9天–增加 2天） 病毒清除时间 越低越好 基于 5项研究中 440名参与者的数据 （随机对照） 9.7 天（均值） 10.6 天（均值） 很低 因严重的偏倚风险 和非常严重的 不精确性 13 羟氯喹对病毒清除 时间的效果 尚不确定。 差异：平均差减少0.7天 （95%置信区间减少 4.3天–增加 4.8天） 导致停药的 不良事件 基于 3项研究中 210名参与者的数据 （随机对照） 被随机分配到羟氯喹组的 108名 参与者中有 2名因不良反应 而停止了治疗。 在安慰剂/标准治疗组的 102名患者中 无人出现这种情况。 很低 因极为严重的 不精确性 14 羟氯喹对导致停药 的 不良事件的影响 尚不确定。 1. 系统综述[1]。基线/对照组：主要研究。死亡率和机械通气的基线风险来自世卫组织“团结”试验中 COVID-19 重症和 危重症患者的数据。 2. 不精确性：严重。95%的置信区间跨越了最小重要差异（死亡率降低 2%）。 3. 不精确性：严重。宽置信区间。 4. 系统综述。我们使用了被纳入的研究的所有随机分配到常规治疗的患者的中位事件率。基线/对照组：干预组的参考对照 组。支持性参考文献：[1] 5. 不精确性：非常严重。宽置信区间。 6. 间接性：严重。不精确性：非常严重。 7. 偏倚风险：严重。非盲研究->心脏毒性检测差异。间接性：严重。各研究用不同的方式测量了严重的心脏毒性。不精确 性：严重。 8. 偏倚风险：严重。由于产生的效果大，且间接证据显示出了一致的结果，担忧有所缓解。不精确性：严重。没有达到最 优信息样本量。升级：效果显著。 9. 偏倚风险：严重。由于产生的影响大，且间接证据显示出了一致的结果，担忧有所缓解。不精确性：严重。没有达到最 优信息样本量。升级：显著效果。 10. 间接性：严重。这一结局没有被系统地收集，并且没有明确谵妄的定义。不精确性：非常严重。 11. 偏倚风险：严重。间接性：严重。各研究以不同的方式衡量临床改善。不精确性：严重。 12. 偏倚风险：严重。不精确性：严重。宽置信区间。 13. 偏倚风险：严重。不精确性：非常严重。 14. 不精确性：极为严重。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 88 of 119 6.14. 洛匹那韦-利托那韦（2020 年 12 月 17 日发布） 信息栏 关于洛匹那韦-利托那韦的建议于2020年12月17日作为世卫组织动态指南的第三版发布，并在《英国医学杂志》中作为快速 建议发表。此前，于2020年10月15日发布了世卫组织“团结”试验预印本，报告了在COVID-19住院患者中使用洛匹那韦-利托 那韦、瑞德西韦和羟氯喹治疗的结果(15)。在本第十一版指南中，没有对洛匹那韦-利托那韦的建议进行改动。 用于COVID-19患者，无论疾病严重程度 强烈建议不使用 我们建议不使用洛匹那韦-利托那韦。（强烈建议不使用） 备注：本建议适用于任何疾病严重程度和任何症状持续时间的患者。 决策证据 利弊 GDG认为缺乏证据表明洛匹那韦-利托那韦能够改善对患者重要的结局，如降低死亡率、机械通气需要和临床改善的时间等。 对死亡率和机械通气需要的效果的证据确定性为中等；其他结局的证据确定性为低或很低。 低确定性证据显示洛匹那韦-利托那韦可能会增加腹泻、恶心和呕吐的风险，这一结论与评价其在艾滋病毒感染患者中的使用 所得出的间接证据一致。腹泻和呕吐可能增加低血容量、低血压和急性肾损伤的风险，特别是在卫生保健资源有限的地方。对病 毒清除的效果和急性肾损伤的影响尚不确定。 亚组分析表明，没有基于疾病严重程度（危重症对比重症/非重症或非重症对比危重症/重症）或年龄（不足70岁对比70岁及以 上）的效果差异。由于没有具有统计意义的亚组效应的证据，我们未使用ICEMAN工具进行正式评价。 证据的确定性 证据来自于一个相关的系统综述和对七个随机对照试验的网络荟萃分析；汇集了7429个不同严重程度的COVID-19住院患者的 数据，并不同程度地向指南小组报告了相关结局(1)。小组一致认为死亡率和机械通气需要的证据确定性为中等，腹泻、恶心和住 院时间的证据确定性为低，对病毒清除、急性肾损伤和临床改善时间的效果估计值的证据确定性很低。大多数结局的证据确定性 由于存在偏倚风险和不精确性（宽置信区间不排除重要的利弊）而被降低。 价值观和偏好 根据一致商定的价值观和偏好（见第7节），GDG推断，几乎所有完全知情的患者都不会愿意接受洛匹那韦-利托那韦治疗， 因为证据表明其对死亡率和机械通气需要很可能没有效果，而且有包括腹泻、恶心和呕吐在内的不良事件风险。小组预计不同患 者之间对这种干预措施的价值观和偏好不会有很大差异。 资源和其他考虑因素 尽管洛匹那韦-利托那韦并不像其他一些被研究的COVID-19治疗药物那么昂贵，而且在大多数卫生保健环境中已经广泛可 得，GDG提出对机会成本的担忧，并提出一定不能把关注点和资源从最佳的支持性治疗上或是对COVID-19重症患者使用皮质类固 醇上转移开来。 理由 当根据证据提出强烈建议不要给COVID-19患者使用洛匹那韦-利托那韦时，小组强调有中等确定性证据表明不能降低死亡率 或机械通气需要。还指出，证据表明治疗可能会带来恶心和腹泻增加的弊端。GDG预见不同患者在价值观和偏好上无重要差异， 并认为其他背景因素（如资源考虑、可获得性、可行性和对卫生公平的影响）不会改变这项建议（见“决策证据”中对这些因素 的总结）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 89 of 119 亚组分析 小组没有发现任何证据表明在不同疾病严重程度以及成年人和老年人之间存在亚组效应，因此没有对此药做出任何亚组建 议。虽然这些试验并没有报告按症状出现时间划分的亚组效应，但很多试验招募了处于病程早期的患者。此强烈建议适用于任何 疾病严重程度和年龄组的患者。 适用性 被纳入的随机对照试验都没有招募过儿童，因此目前不能确定这项建议是否适用于儿童。然而，小组没有理由认为COVID-19 的儿童患者对洛匹那韦-利托那韦的治疗会有任何不同的反应。对于孕妇也有类似的考虑，虽然没有对孕妇群体的直接研究数据， 但没有理由认为她们的用药反应会与其他成年人不同。使用洛匹那韦-利托那韦治疗艾滋病毒感染的患者，一般而言在接受 COVID-19治疗时应继续用药。 不确定性 剩余不确定性请参见文件结尾部分（第9节）。GDG认为，未来的研究不太可能会找到一个可能受益于洛匹那韦-利托那韦的 患者亚组。 额外考虑因素 对于未诊断或未经治疗的艾滋病毒感染者，单独使用洛匹那韦-利托那韦可能会增强艾滋病毒对重要的抗逆转录病毒药物的耐 药性。广泛使用洛匹那韦-利托那韦治疗COVID-19可能导致艾滋病毒感染者的药物短缺。 临床问题/PICO 对象： COVID-19患者（所有疾病严重程度） 干预： 洛匹那韦-利托那韦 对照： 标准治疗 摘要 证据摘要 对洛匹那韦-利托那韦的LNMA基于7项试验，共有7429名参与者。值得注意的是，被纳入的研究都没有招募19岁以下的儿 童或青少年（见此表）。建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，洛匹那韦-利托 那韦与常规治疗相比对各种疾病严重程度的COVID-19患者的相对效果和绝对效果，并给出了证据确定性评级。请参见第7节获 取作为绝对效果估计值依据的基线风险估计值来源。 亚组分析 对于洛匹那韦-利托那韦，GDG请求根据年龄（儿童对比年轻人[如不足70岁]对比老年人[如70岁或以上]）和疾病严重程度 （COVID-19非重症对比重症对比危重症）进行亚组分析。GDG讨论了其他可能的相关亚组，包括按从症状出现到开始治疗的 时间和联合用药来划分亚组，但认识到如果没有个体参与者的数据和/或来自个别试验的更详细报告，不可能进行这样的亚组分 析。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 洛匹那韦-利托那韦 证据的确定性 （证据质量） 纯文本摘要 死亡率 优势比：1 （95%置信区间 0.82-1.2） 基于 4项研究中 8061名参与者的数据 1 （随机对照） 106 每 1000人 106 每 1000人 中等 由于临界的偏倚 风险和不精确性 2 洛匹那韦-利托那韦 很可能对死亡率 没有影响。 差异：每1000人死亡减少0例 （95%置信区间 减少 17例-增加 19例） 机械通气 相对危险度：1.16 （95%置信区间 105 每 1000人 122 每 1000人 中等 由于临界的偏倚 洛匹那韦-利托那韦 很可能不会减少 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 90 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 洛匹那韦-利托那韦 证据的确定性 （证据质量） 纯文本摘要 0.98-1.36） 基于 3项研究中 7579名参与者的数据 （随机对照） 差异：每1000人增加17例 （95%置信区间减少 2例-增加 38例） 风险和不精确性 3 机械通气。 病毒清除 优势比：0.35 （95%置信区间 0.04-1.97） 基于 2项研究中 171名 参与者的数据 4 （随机对照） 483 每 1000人 246 每 1000人 低 由于非常严重的 不精确性 5 洛匹那韦-利托那韦 对病毒清除的效果 非常不确定。 差异：每1000人减少237例 （95%置信区间减少 447例–增加 165例） 急性肾损伤 相对危险度 基于 2项研究中 259名 参与者的数据 （随机对照） 45 每 1000人 25 每 1000人 很低 由于严重的偏倚 风险和非常严重的 不精确性 6 洛匹那韦-利托那韦 对急性肾损伤的 影响尚不确定。 差异：每1000人减少20例 （95%置信区间减少 70例–增加 20例） 腹泻 优势比：4.28 （95%置信区间 1.99-9.18） 基于 4项研究中 370名 参与者的数据 （随机对照） 67 每 1000人 235 每 1000人 中等 由于严重的偏倚 风险和不精确性； 由于显著效果 而升级 7 洛匹那韦-利托那韦 可能增加腹泻风险。 差异：每1000人增加168例 （95%置信区间增加 58例–增加 330例） 恶心/呕吐 相对危险度 基于 4项研究中 370名 参与者的数据 （随机对照） 17 每 1000人 177 每 1000人 中等 由于严重的偏倚 风险和不精确性 8 洛匹那韦-利托那韦 可能增加恶心/ 呕吐风险。 差异：每1000人增加160例 （95%置信区间增加 100例–增加 210例） 临床改善时间 越低越好 基于 1项研究中 199名 参与者的数据 （随机对照） 11 天（均值） 10 天（均值） 很低 由于严重的偏倚风 险和非常严重的 不精确性 9 洛匹那韦-利托那韦 对临床改善时间的 影响非常不确定。 差异：平均差减少1天 （95%置信区间减少 4.1天–增加 3.2天） 住院持续时间 越低越好 基于 2项研究中 5239名参与者的数据 （随机对照） 12.8 天（均值） 12.5 天（均值） 低 由于严重的偏倚 风险和不精确性 10 洛匹那韦-利托那韦 可能对住院持续 时间没有影响。 差异：平均差减少0.3天 （95%置信区间减少 3.0天–增加 2.5天） 1. 系统综述。基线/对照组：主要研究[15]。死亡率和机械通气的基线风险来自世卫组织“团结”试验中 COVID-19 重症和 危重症患者的数据。支持性参考文献：[1]。 2. 不精确性：严重。95%的置信区间跨越了最小重要差异（死亡率降低 2%） 3. 不精确性：严重。宽置信区间。 4. 系统综述。基线/对照组：干预组的参考对照组。我们使用了被纳入的研究的所有随机分配到常规治疗的患者的中位事 件率。支持性参考文献：[1]。 5. 不精确性：非常严重。宽置信区间。 6. 偏倚风险：严重。不精确性：非常严重。宽置信区间。 7. 偏倚风险：严重。由于产生的效果大，且间接证据显示出了一致的结果，担忧有所缓解。不精确性：严重。患者和事件 量太少。升级：效果显著。 8. 偏倚风险：严重。由于产生的效果大，且间接证据显示出了一致的结果，担忧有所缓解。不精确性：严重。患者和事件 量太少。升级：效果显著。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 91 of 119 9. 偏倚风险：严重。不精确性：非常严重。宽置信区间，患者数量少。 10. 偏倚风险：严重。不精确性：严重。宽置信区间。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 92 of 119 6.15. 全身性皮质类固醇（2020 年 9 月 2 日发布） 信息栏 关于皮质类固醇的建议首次于2020年9月2日作为世卫组织动态指南发布，并于2020年9月5日作为《英国医学杂志》快速建 议发表。此前，“康复”试验的初步报告已经发布，后来又作为同行评议论文发表(14)。在这份第十一版指南中，没有对皮质 类固醇的建议进行修改。 尽管建议保持不变，但在本动态指南的第六次迭代之前，对COVID-19患者使用皮质类固醇的证据摘要进行了更新。死亡 率的基线风险估计值现在基于世卫组织“团结”试验（对本指南中的其他药物也是一样）(15)，而不是最初的ISARIC队列研究 (149)，后者可能高估了当前全球层面的死亡风险。这一更新对确定证据摘要中的死亡率基线风险也很必要，以在此基础上制定 对白介素-6受体阻滞剂的强烈建议，从而补充对COVID-19重症或危重症患者的标准治疗（在标准治疗中使用皮质类固醇可将死 亡率相对降低21%）。 用于COVID-19重症或危重症患者 强烈建议使用 我们建议使用全身性皮质类固醇治疗。（强烈建议使用） 实用信息 途径：全身性皮质类固醇可以通过口服和静脉注射给药。值得注意的是，虽然地塞米松的生物利用度非常高（即口服和静脉 注射后血浆中达到相似的浓度），但危重症患者可能由于肠道功能障碍而无法吸收任何营养素或药物。因此，如果怀疑肠功能障 碍，临床医生可以考虑静脉注射全身性皮质类固醇而不是口服。 持续时间：虽然更多的患者是以每天接受6毫克地塞米松的形式接受皮质类固醇治疗，最长达10天，但七个试验中所评估的用 药方案的总持续时间在5至14天不等，一般在出院时停止治疗（即治疗持续时间可小于方案中规定的持续时间）。 剂量：每日一次的地塞米松制剂也许能增加依从性。6毫克地塞米松（在糖皮质激素效应上）相当于150毫克氢化可的松（即 每8小时50毫克）、40毫克泼尼松龙或32毫克甲基强的松龙（每6小时8毫克或12小时16毫克）。 监测：不管患者是否已知患有糖尿病，都应谨慎监测COVID-19重症和危重症患者的血糖水平。 时机：小组讨论了从症状开始起治疗的时机。“康复”试验研究人员报告了一个亚组分析，表明在症状出现后7天或更长时间 后开始治疗可能比症状出现后7天内开始治疗更有益。一个前瞻性荟萃分析内的事后亚组分析不支持这一假设。虽然一些小组成员 认为，将全身性皮质类固醇的使用推迟到病毒复制被免疫系统遏制之后可能是合理的，但许多成员指出，在实践中，往往无法确 定症状最初何时出现，而且表示严重程度的体征往往出现较晚（即说明严重程度和时间之间存在共线性）。小组的结论认为，鉴 于这些证据，在治疗COVID-19重症或危重症患者时宁可使用皮质类固醇（即使是在症状出现后的7天内），而在治疗非重症患者 时宁可不使用皮质类固醇（即使是在症状出现7天后）。 决策证据 利弊 投票赞成有条件建议使用的小组成员认为，评价全身性皮质类固醇治疗COVID-19的试验报告的潜在危害的信息有限。在两次 小组会议之间，关于全身性皮质类固醇对败血症、急性呼吸窘迫综合征和社区获得性肺炎的潜在危害的间接证据被添加到结论摘 要表中(150)(151)。虽然这些数据的确定性普遍为低，但仍是令人放心的，数据表明皮质类固醇不会增加不良事件的风险，除了可 能增加高血糖发病率（中等确定性证据；绝对效果估计值为每1000名患者增加46例，95%置信区间：增加23至72例）和高钠血症 （中等确定性证据；每1000名患者增加26例，95%置信区间：增加13至增加41例）。小组成员还指出，鉴于全身性皮质类固醇对 死亡率的预期效果，大多数患者不会为了避免被认为对大多数患者来说明显不如死亡重要的不良事件而拒绝这种干预措施。 与提议用于治疗COVID-19的新制剂不同，临床医生在全身性皮质类固醇方面有着丰富的经验，小组对其整体安全性情况感到 放心。此外，小组相信，使用这些指南的临床医生会了解全身性皮质类固醇治疗的其他潜在副作用和禁忌症，这些由于地方性微 生物菌群的不同而在不同地域可能有所不同。尽管如此，临床医生在对糖尿病患者或基础性免疫缺陷患者使用皮质类固醇时应谨 慎。 最终，小组根据28天死亡率在危重症患者中降低8.7%和重症非危重症患者中降低6.7%的中等确定性证据做出了建议。在本动 态指南的第五次更新中，根据世卫组织“团结”试验更新了死亡率基线风险估计值，“团结”试验被认为是所有面临COVID-19大 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 93 of 119 流行的国家的最佳预后来源。这样一来COVID-19重症或危重症患者的28天死亡率总体降低了3.3%，证据仍为中等确定性，并被小 组认为对患者有明显益处，因此对既定建议没有影响。 价值观和偏好 小组从个体患者的角度来看待价值观和偏好，但考虑到大流行给全球卫生保健系统带来的负担，也高度重视资源分配和公平 问题。皮质类固醇对死亡率的益处被认为对患者是至关重要的，预计COVID-19重症患者在接受该药治疗的偏好上几乎或完全不存 在任何差异。 资源和其他考虑因素 对资源的影响、可行性、公平和人权 在本指南中，小组从个体患者的角度出发，但也高度重视资源的分配。从这个角度上说，关注了广泛提供COVID-19治疗所产 生的机会成本。总体而言，其他COVID-19的候选疗法价格昂贵，往往尚未得到上市许可，很难获得，而且要求先进的医疗基础设 施。相比之下，全身性皮质类固醇治疗费用低廉，易于给药，而且在全球范围内容易获得(152)。地塞米松和泼尼松龙是国家基本 药物清单中最常见的药物，有95%的国家将其列入清单。世界卫生组织1977年首次将地塞米松列为基本药物，2年后将泼尼松龙列 为基本药物(153)。 因此，全身性皮质类固醇是相对而言为数不多的、有可能减少不公平现象、改善卫生公平的COVID-19干预措施之一。这些考 虑因素影响了这项建议的强度。 可接受性 鉴于全身性皮质类固醇给药简便、疗程相对较短、治疗7-10天的总体安全性好，小组得出结论认为此干预措施的可接受性 高。 理由 这项建议是在就支持全身性皮质类固醇的建议强度进行投票后达成的。在投票的23名小组成员中，19名（83%）投票赞成强 烈建议，4名（17%）投票赞成有条件的建议。4票表达谨慎的原因总结如下，一些对强烈建议投了赞成票的小组成员也认同这些 原因。 适用性 投票赞成有条件建议使用的小组成员认为，许多可能有资格参加“康复”试验的患者被主治医生排除在外，没有参加对皮质 类固醇的评价，由于没有关于被排除患者特征的详细信息，这些成员认为因此无法给出强烈建议。其他小组成员认为，在实际试 验中这样一个被排除在外的患者比例是常态，而不是例外，而且虽然没有收集排除患者原因的详细信息，但拒绝让其参与试验的 主要原因可能是担心明确符合使用皮质类固醇指征的患者一旦停止用药会有安全问题（得到“康复”试验首席研究员的个人通信 证实）。小组成员指出，对于7-10天的皮质类固醇治疗疗程，几乎没有绝对禁忌症，建议的对象是普通患者群体，而且不言而 喻，即使是强烈建议也不应适用于主治医生确定存在禁忌症的患者。 最终，小组得出结论，这项建议适用于COVID-19重症和危重症患者，不论其是否住院。基本假设是，这些患者将在医院接受 治疗，并接受氧气形式的呼吸支持；采用有创或无创通气（如果有这些选择的话）。按照GRADE的指导原则，在做出强烈建议 时，小组推断，所有或几乎所有完全知情的COVID-19重症患者会选择使用全身性皮质类固醇。不言而喻，即使在强烈建议的情况 下，对某些患者来说这种干预措施可能是禁忌。7-10天疗程的全身性皮质类固醇治疗的绝对禁忌症是罕见的。在考虑潜在的禁忌 症时，临床医生必须确定此禁忌症是否足以剥夺患者获得一种潜在的救命疗法。 此建议的适用性对于那些研究试验中代表不足的人群，如儿童、结核病患者和免疫缺陷的人群来说不那么明确。尽管如此， 临床医生也会考虑剥夺这些患者潜在的救命疗法所带来的风险。相比之下，小组得出结论，认为此建议绝对应该适用于某些没有 被纳入试验的患者，例如由于资源有限而不能住院或接受氧气治疗的COVID-19重症和危重症患者。 此建议不适用于以下方式使用皮质类固醇：经皮或吸入给药、大剂量或长期用药、或预防。 临床问题/PICO 对象：COVID-19重症或危重症患者（更新后的基线死亡风险） 干预：全身性皮质类固醇 对照：标准治疗 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 94 of 119 摘要 证据摘要 该指南的制定缘于2020年6月22日“康复”试验初步报告的发布，报告现已作为同行评议论文发表(14)。皮质类固醇被列入 《世卫组织基本药物标准清单》，在全球范围内以低廉的价格容易获得，并且所有利益相关者群体都对它相当关注。GDG参考 了两个荟萃分析，共汇集了八项使用全身性皮质类固醇治疗COVID-19的随机试验（7184名参与者）的数据(1)(154)。小组的讨 论还参考了另外两个均已经发表的荟萃分析，汇集了在不同但相关的患者群体中全身性皮质类固醇的安全性数据。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，全身性皮质类固醇与常规治疗相比对 COVID-19重症和危重症患者的相对效果和绝对效果，并给出了证据确定性评级。请参见第7节获取作为绝对效果估计值依据的 基线风险估计值来源。 2020年7月17日，小组审议了八个随机对照试验（7184名患者）的证据，这些试验评价了治疗COVID-19时使用全身性皮质 类固醇相对于常规治疗的效果。“康复”是7个试验中最大的一个，按亚组（重症和非重症）报告了死亡率数据，该试验评价 了联合王国6425名住院患者（2104人随机采用地塞米松治疗，4321人随机采用常规治疗）最多10日里每日一次（口服或静脉注 射）6毫克地塞米松的疗效(14)。在随机分配时，16%的患者正在接受有创机械通气或体外膜氧合，60%的只接受氧气（辅以或 未辅以无创通气）支持，24%的未接受这两项中的任何一项治疗。 来自其他7个较小型试验的数据包括了63名非危重症患者和大约700名危重症患者（对危重症的定义因试验而异）。对于后 者，患者的招募截止到2020年6月9日，其中大约五分之四接受有创机械通气；患者中大约一半随机接受皮质类固醇治疗，另外 一半随机接受非皮质类固醇治疗。皮质类固醇疗法包括：甲基强的松龙，每12小时40毫克，连续3天，之后每12小时20毫克， 连续3天（GLUCOCOVID试验）(155)；地塞米松，每日20毫克，连续5天，之后每日10毫克，连续5天（两个试验：DEXA- COVID19和CoDEX）(156)(157)；氢化可的松，每日200毫克，连续4-7天，之后每天100毫克，连续2-4天，再后每天50毫克，连 续2-3天（一项试验，CAPE-COVID）(158)；氢化可的松每日200毫克，连续7天（一项试验，REMAP-CAP）(16)；甲基强的松 龙每12小时40毫克，连续5天（一项试验，类固醇-SARI）(159)。 有七项试验是在单个国家进行的（巴西、中国、丹麦、法国、西班牙），而REMAP-CAP是一项国际试验（在14个欧洲国 家、澳大利亚、加拿大、新西兰、沙特阿拉伯和联合王国进行招募）。除了一项试验在21天和另一项试验在30天外，所有试验 均在随机分组后28天报告了死亡率。因为一项试验（GLUCOCOVID，人数=63）的死亡率数据未按亚组报告，小组只审议了该 试验中与机械通气结局有关的数据(155)。另有一项试验对疑似SARS-CoV-2感染的住院患者进行了随机研究，并于2020年8月12 日发布了结果（MetCOVID）[160]，但因为这项试验是在搜索试验登记册之后才登记的，所以被作为补充内容纳入了前瞻性荟 萃分析出版物。补充内容显示纳入这个试验后并不会改变结果，只是降低了不一致性。 亚组分析 虽然所有其他试验均只评价了危重症患者使用全身性皮质类固醇的情况，但“康复”试验招募的是COVID-19住院患者。 小组审议了“康复”试验的一个亚组分析结果，结果表明全身性皮质类固醇的相对效果随着随机分组时患者接受的呼吸支持水 平的不同而变化。根据同行评审过的可信亚组效应标准(110)，小组认为亚组效应的可信度足以支持对治疗COVID-19重症和非 重症患者分别制定建议。 然而，小组认识到，在大流行期间，获得卫生保健服务的机会可能随着时间的推移以及在不同国家之间存在很大差异，因 此决定不根据获得卫生干预措施（即住院和呼吸支持）的机会来界定建议所涉及的患者人群。因此，小组将“康复”试验中的 效果差异归因于疾病严重程度。 但是小组也承认，对于疾病严重程度和呼吸支持干预措施的使用存在不同的定义。2020年5月27日发布的《世卫组织2019 冠状病毒病临床指导文件》（第3版）根据临床指标界定了COVID-19的严重程度，但将血血氧饱和度阈值从94%修改为90%，以 便与之前的世界卫生组织指导文件保持一致(6)。世卫组织制定的严重程度标准请参见第5节，在实践中应用建议时请参见信息图 了解疾病严重程度的三个分组。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 95 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 全身性皮质类固醇 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 相对危险度：0.79 （95%置信区间 0.7-0.9） 基于 7项研究中 1703名 参与者的数据 1 随访 28天 160 每 1000人 126 每 1000人 中等 由于严重的 偏倚风险 2 全身性皮质类固醇 很可能会降低 OVID-19危重症 患者的 28天 死亡率。 差异：每 1000 人减少 34 例 （95%置信区间减少 48例-减少 16例） 有创机械 通气需要 28天 相对危险度：0.74 （95%置信区间 0.59-0.93） 基于 2项研究中 5481名 参与者的数据 随访 28天 116 每 1000人 86 每 1000人 中等 由于严重的 偏倚风险 3 全身性皮质类固醇 很可能会降低机械 通气需要。 差异：每 1000 人减少 30 例 （95%置信区间减少 48例–减少 8例） 胃肠道出血 相对危险度：1.06 （95%置信区间 0.85-1.33） 基于 30项研究中 5403名 参与者的数据 48 每 1000人 51 每 1000人 低 由于严重的间接性， 由于严重的 不精确性 4 全身性皮质类固醇 可能不会增加胃肠道 出血的风险。 差异：每1000人增加3例 （95%置信区间减少 7例–增加 16例） 超级感染 相对危险度：1.01 （95%置信区间 0.9-1.13） 基于 32项研究中 6027名参与者的数据 186 每 1000人 188 每 1000人 低 由于严重的间接性和 严重的不精确性 5 全身性皮质类固醇 可能不会增加超级 感染的风险。 差异：每1000人增加2例 （95%置信区间减少 19例–增加 24例） 高血糖 相对危险度：1.16 （95%置信区间 1.08-1.25） 基于 24项研究中 8938名参与者的数据 286 每 1000人 332 每 1000人 中等 由于严重的间接性 6 全身性皮质类固醇 很可能会增加 高血糖的风险。 差异：每1000人增加46例 （95%置信区间增加 23–增加 72例） 高钠血症 相对危险度：1.64 （95%置信区间 1.32-2.03） 基于 6项研究中 5015名 参与者的数据 40 每 1000人 66 每1000人 中等 由于严重的间接性 7 全身性皮质类固醇 很可能会增加高钠 血症的风险。 差异：每 1000 人增加 26 例 （95%置信区间增加 13–增加 41例） 神经肌肉无力 相对危险度：1.09 （95%置信区间 0.86-1.39） 基于 8项研究中 6358名 参与者的数据 69 每 1000人 75 每 1000人 低 由于严重的间接性和 严重的不精确性 8 全身性皮质类固醇 可能不会增加神经 肌肉无力的风险。 差异：每1000人增加6例 （95%置信区间减少 10例–增加 27例） 神经精神病学 效应 相对危险度：0.81 （95%置信区间 0.41-1.63） 基于 7项研究中 1813名 参与者的数据 35 每 1000人 28 每 1000人 低 由于严重的间接性和 严重的不精确性 9 全身性皮质类固醇 可能不会增加神经 精神病学效应的 风险。 差异：每1000人减少7例 （95%置信区间减少 21例–增加 22例） 住院持续时间 度量单位：天数 越低越好 基于 1项研究中 6425名 参与者的数据 13 天 12 天 低 由于严重的偏倚风险 和严重的不精确性 10 全身性皮质类固醇 可能会带来住院持续 时间的重要缩短。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 96 of 119 1. 系统综述[1]。基线/对照组：主要研究[15]。2021年 5月更新的死亡率基线风险估计值：现在来自世卫组织“团结”试验 （被认为是最佳来源），重症和危重患者 28天死亡率为 14.6%。这一估计值对“团结”试验中 50%接受皮质类固醇作为 标准治疗的情况做出了调整。 2. 偏倚风险：严重。缺乏盲法。 3. 偏倚风险：严重。缺乏盲法。 4. 间接性：严重。不精确性：严重。 5. 间接性：严重。不精确性：严重。 6. 间接性：严重。 7. 间接性：严重。 8. 间接性：严重。不精确性：严重。 9. 间接性：严重。不精确性：严重。 10. 偏倚风险：严重。缺乏盲法。不精确性：严重。置信区间不包括益处。 用于COVID-19非重症感染患者 有条件建议不使用 我们建议不使用全身性皮质类固醇。（有条件建议不使用） 实用信息 有条件建议不对COVID-19非重症患者使用皮质类固醇，但如考虑采用此疗法时适用以下实用信息： 途径：全身性皮质类固醇可以口服和静脉注射。值得注意的是，虽然地塞米松的生物利用度很高（即口服和静脉注射后血浆 中达到相似的浓度），但危重症患者可能由于肠道功能障碍而无法吸收任何营养素或药物。因此，如果怀疑肠功能障碍，临床医 生可以考虑静脉注射全身性皮质类固醇而不是口服。 持续时间：虽然更多的患者每天接受6毫克地塞米松形式的皮质类固醇，最长可达10天，但七个试验中所评估的方案总持续时 间在5至14天不等，一般在出院时即停止治疗（即治疗持续时间可小于方案规定的持续时间）。 剂量：每日使用一次地塞米松制剂也许能增加依从性。6毫克地塞米松（在糖皮质激素效应上）相当于150毫克氢化可的松 （如每8小时50毫克）、40毫克泼尼松或32毫克甲基强的松龙（如每6小时8毫克或每12小时16毫克）。不管患者是否已知患有糖尿 病，都应谨慎监测COVID-19重症和危重症患者的血糖水平。 时机：小组讨论了从症状开始起治疗的时机。“康复”试验研究人员报告了一个亚组分析，表明在症状出现后7天或更长时间 后开始治疗可能比症状出现后7天内开始治疗更有益。一个前瞻性荟萃分析内的事后亚组分析不支持这一假设。虽然一些小组成员 认为，将全身性皮质类固醇的使用推迟到病毒复制被免疫系统遏制之后可能是合理的，但许多成员指出，在实践中，往往无法确 定症状最初何时出现，而且表示严重程度的体征往往出现较晚（即说明严重程度和时间之间存在共线性）。小组的结论认为，鉴 于这些证据，在治疗COVID-19重症或危重症患者时宁可使用皮质类固醇（即使是在症状出现后的7天内），而在治疗非重症患者 时宁可不使用皮质类固醇（即使是在症状出现7天后）。 应考虑到使用皮质类固醇后病情可能恶化的其他地方性感染。例如，对于与皮质类固醇治疗相关的粪类圆线虫高度感染，如 果使用类固醇，在流行地区可以考虑诊断或经验性治疗。 决策证据 利弊 小组基于低确定性证据制定了建议，这些证据表明，在COVID-19非重症病患者中，28天的死亡率可能会增加3.9%。由于严重 的不精确性（即证据不能排除死亡率降低的可能性）和缺乏盲法而造成的偏倚风险，降低了这一特定亚组的证据确定性。在有条 件提出建议不要不加区别地使用全身性皮质类固醇时，小组推断大多数完全知情的非重症患者不希望使用全身性皮质类固醇，但 许多人可能想要通过与主治医生共同决策来考虑使用此干预措施(161)(6)。 注：世卫组织建议在没有孕产妇感染的临床证据，并且有足够的分娩和新生儿护理的情况下，在妊娠24至34周期间，对有早 产风险的孕妇进行产前皮质类固醇治疗。然而，在妇女患有COVID-19轻症或中度感染的情况下，产前皮质类固醇的临床益处可能 大于对母亲潜在危害的风险。在这种情况下，应与孕妇讨论对孕妇和早产儿的利弊权衡问题，以确保做出明智的决定，评估结果 可能因孕妇的临床状况、她和家人的愿望以及可用的卫生保健资源而异。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 97 of 119 证据的确定性 见“利弊”部分。 价值观和偏好 提出弱建议或有条件的建议是由于不同患者的价值观和偏好可能会有差异。小组判断，大多数非重症患者会不愿使用全身性 皮质类固醇。然而，许多人可能会在与他们的主治医生做出共同决策后愿意使用。 资源和其他考虑因素 对资源的影响、可行性、公平和人权 小组还认为，为了确保COVID-19重症和危重症患者能够获得全身性皮质类固醇治疗，避免对那些在目前的证据下似乎无法从 这种干预措施中获得任何益处的患者采取此干预手段是合理的。 理由 这项建议获得一致同意。 适用性 这项建议适用于非重症患者，不论其是否住院。小组指出，COVID-19非重症患者通常不需要急性住院治疗或呼吸支持，但在 某些地区，这些患者可能只是出于隔离目的而住院，在这种情况下，不应对他们进行全身性皮质类固醇治疗。小组的结论是，对 于因其他原因已经使用全身性皮质类固醇治疗的COVID-19非重症患者（例如，慢性阻塞性肺病患者或其他慢性自身免疫性疾病患 者不需要中断全身性口服皮质类固醇疗程），不应停止使用全身性皮质类固醇治疗。如果COVID-19非重症患者的临床情况恶化 （即呼吸频率增加，呼吸窘迫或低氧血症的体征），他们应该接受全身性皮质类固醇治疗（见针对COVID-19重症和危重症患者的 建议）。 临床问题/PICO 对象：COVID-19非重症患者 干预：全身性皮质类固醇 对照：标准治疗 摘要 证据摘要 请参见上文（针对COVID-19重症和危重症患者的建议）中的证据摘要以了解更多关于八个随机对照试验的信息，这些随 机对照试验汇集在两个系统综述和荟萃分析中。该证据摘要还提供了作为安全性结局和亚组分析结果依据的额外的系统综述信 息，由此小组为COVID-19非重症患者和为重症危重症患者分别制定建议。 建议分级的评估、制定和评价（GRADE）的结论摘要表显示了对于人们关注的结局，全身性皮质类固醇与常规治疗相比对 COVID-19非重症患者的相对效果和绝对效果，并给出了证据确定性评级。 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 全身性皮质类固醇 证据的确定性 （证据质量） 纯文本摘要 死亡率 28天 相对危险度：1.22 （95%置信区间 0.93-1.61） 基于 1项研究中 1535名 参与者的数据 1 随访 28天 23 每 1000人 28 每 1000人 低 由于严重的偏倚风险 和严重的不精确性 2 全身性皮质类固醇 可能会增加 COVID-19非重症 患者的 28天 死亡率。 差异：每1000人增加5例 （95%置信区间减少 2例-增加 14例） 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 98 of 119 结局 时限 研究结果和衡量标准 对照组 标准治疗 干预组 全身性皮质类固醇 证据的确定性 （证据质量） 纯文本摘要 有创机械通气 需求 28天 相对危险度：0.74 （95%置信区间 0.59-0.93） 基于 2项研究中 5481名 参与者的数据 随访 28天 116 每 1000人 86 每 1000人 中等 由于严重的 偏倚风险 3 全身性皮质类固醇 很可能会降低机械 通气需求。 差异：每 1000 人减少 30 例 （95%置信区间 减少 48-减少 8例） 胃肠道出血 相对危险度：1.06 （95%置信区间 0.85-1.33） 基于 30项研究中 5403名参与者的数据 4 48 每 1000人 51 每 1000人 低 由于严重的间接性和 严重的不精确性 5 皮质类固醇可能不会 增加消化道 出血的风险。 差异：每1000人增加3例 （95%置信区间减少 7例-增加 16例） 超级感染 相对危险度：1.01 （95%置信区间 0.9-1.13） 基于 32项研究中 6027名参与者的数据 186 每 1000人 188 每 1000人 低 由于严重的间接性， 由于严重的 不精确性 6 皮质类固醇 可能不会增加超级 感染的风险。 差异：每1000人增加2例 （95%置信区间减少 19例-增加 24例） 高血糖 相对危险度：1.16 （95%置信区间 1.08-1.25） 基于 24项研究中 8938名患者的数据 286 每 1000人 332 每 1000人 中等 由于严重的间接性 7 皮质类固醇 很可能会增加 高血糖的风险。 差异：每1000人增加46例 （95%置信区间增加 23-增加 72例） 高钠血症 相对危险度：1.64 （95%置信区间 1.32-2.03） 基于 6项研究中 5015名 参与者的数据 40 每 1000人 66 每 1000人 中等 由于严重的间接性 8 皮质类固醇 很可能会增加高钠 血症的风险。 差异：每1000人增加26人 （95%置信区间增加 13-增加 41例） 神经肌肉无力 相对危险度：1.09 （95%置信区间 0.86-1.39） 基于 8项研究中 6358名 参与者的数据 69 每 1000人 75 每 1000人 低 由于严重的间接性和 严重的不精确性 9 皮质类固醇 可能不会增加神经 肌肉无力的风险。 差异：每1000人增加6例 （95%置信区间减少 10例-增加 27例） 神经精神病学 影响 相对危险度：0.81 （95%置信区间 0.41-1.63） 基于 7项研究中 1813名 参与者的数据 35 每 1000人 28 每 1000人 低 由于严重的间接性和 严重的不精确性 10 皮质类固醇可能不会 增加神经精神病学 影响的风险。 差异：每1000人减少7例 （95%置信区间减少 21例-增加 22例） 住院持续时间 度量单位：天数 越低越好 基于 1项研究中 6425名 参与者的数据 （随机对照） 13 天 12 天 低 由于严重的偏倚风险 和严重的不精确性 11 类固醇可能会带来 住院持续时间的 显著缩短。 1. 系统综述[1]。线/对照组：主要研究[15]。死亡和机械通气的基线风险来自世卫组织“团结”的对照组。 2. 偏倚风险：严重。缺乏盲法。不精确性：严重。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 99 of 119 3. 偏倚风险：严重。缺乏盲法。 4. 系统综述。基线/对照组：干预组的参考对照组。支持性参考文献：[1]。 5. 间接性：严重。不精确性：严重。 6. 间接性：严重。不精确性：严重。 7. 间接性：严重。 8. 间接性：严重。 9. 间接性：严重。不精确性：严重。 10. 间接性：严重。不精确性：严重。 11. 偏倚风险：严重。缺乏盲法。不精确性：严重。置信区间不包括益处。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 100 of 119 7. 方法：本指南是如何编制的 本世卫组织动态指南根据可信赖的指南制定标准和方法制定，利用创新流程实现建议的高效率动态更新。这些方法符合《世 卫组织指南制定手册》和准则审查委员会预先批准的方案（规划提案）(161)。 相关指南 世卫组织关于COVID-19治疗的这份动态指南与更广泛、更全面的《COVID-19临床管理：动态指南》相关，后者的内容范围 更广，并定期更新(6)。世卫组织的《疗法与2019冠状病毒病（COVID-19）：动态指南》的前十个版本涉及皮质类固醇、瑞德西 韦、羟氯喹、洛匹那韦/利托那韦、伊维菌素、白介素-6受体阻滞剂、卡西瑞单抗-伊德维单抗（中和单克隆抗体）、恢复期血浆、 JAK抑制剂、索托维单抗、莫努匹拉韦、瑞德西韦和奈玛特韦-利托那韦，可通过世卫组织网站查阅(4)。 关于使用药物预防（而不是治疗）COVID-19的指南包含在一份单独的文件《世卫组织动态指南：预防2019冠状病毒病的药 物》中，可通过世卫组织网站和《英国医学杂志》查阅(8)。 时机 这是一份动态指导文件；一旦新的证据出现需要对建议进行修改，就会对指南进行动态更新并在全球传播(162)。目标是从试 验数据的公开发表触发指南制定过程到世卫组织指南发布时保持在六周的时间范围内，同时要遵守可信赖的指南制定标准（世卫 组织指南制定手册）(161)(163)。 逐步开展的方法 下面是为高效率和及时制定并传播动态的、值得信赖的指导文件所采用的方法，其中涉及同步进行的流程。 第 1步：证据监测和绘图以及触发证据合成 在进行动态的系统综述和网络荟萃分析的背景下，请经验丰富的信息专家，对所有新出现的随机对照试验持续进行全面的日 常监测，这些专家审查针对COVID-19干预措施的新的随机对照试验的所有相关信息源。采用尚未经过同行审查的预印本数据以推 动突发公共卫生事件时的快速数据共享，可加速COVID-19治疗干预措施的评估和临床应用。指南会定期更新，以评估在此期间经 过了同行评议的数据和新数据。一旦发现了需要改变实践的证据，或国际关注度增加，世卫组织疗法指导委员会将启动指南制定 流程。制定或更新特定建议的触发因素基于以下因素（三者中的任何一个都可以启动建议制定）： • 有可能改变实践； • 关于疗法的随机对照试验数据充分，能为高质量的证据合成动态系统综述提供依据； • 对全球受众有意义。 第 2步：召集 GDG 世卫组织选择GDG的成员时确保具备了全球地域代表性、性别平衡以及合适的技术专长和临床专长，并包括了患者代表。对 于每种干预措施，技术部门收集并管理利益申报，没有发现GDG成员及联合主席存在利益冲突。除了分发利益申报表之外，在会 议期间，世卫组织秘书处也介绍了利益申报程序，并给了GDG成员一个机会来申报任何未以书面形式提交的利益申报。没有任何 利益冲突被口头申报。网络搜索也没有发现任何可能被视为在建议制定过程中会影响个人客观性和独立性的利益。 预先选好的专家GDG（见第10节）于2022年4月7日召开会议讨论氟伏沙明和秋水仙碱。会议审议了建议分级的评估、制定和 评价方法（GRADE）的基本内容，包括拟定关于对象、干预、对照、结局（PICO）的问题和建立相关亚组，以及将对患者重要 的结局进行了优先排序（见下文第4步）。GDG随后审查了各项分析，包括在结论摘要表中提出的预先指定的亚组分析，并审议了 针对该干预措施的个体患者的观点和可行性问题，并制定了建议。指南指定小组也审查了作用机制和安全方面的非临床证据。 第 3步：证据合成 应世卫组织疗法指导委员会的请求，动态系统综述/网络荟萃分析团队进行了独立的系统性评议，以了解这些干预措施的利弊 (1)。系统性评议团队由系统性评议专家、临床专家、临床流行病学家和生物统计学家构成。团队成员拥有GRADE方法学的专知， 并尤其擅长评定网络荟萃分析中的证据的确定性等级，包括对治疗方案的直接和间接比较。网络荟萃分析团队讨论了GDG首次会 议的审议情况，特别侧重于GDG优先考虑的结局和亚组，并生成GRADE证据摘要，从而为建议的制定提供信息。在随机对照试验 未对治疗方法进行头对头比较的情况下，LNMA团队进行了间接比较，并生成了更多GRADE证据摘要，为GDG制定建议提供参 考。方法团队使用ICEMAN工具对亚组的可信度进行了评定(110)。技术部门收集和管理利益申报表(DOIs)，未发现SR团队成员存 在利益冲突。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 101 of 119 第 4步：最终建议 GRADE方法为确立证据的确定性和生成建议的方向和强度提供了框架(164)(165)。如GDG未能达成共识，将采用一些基于事 先确定的投票规则的程序。实际的情况是无需进行投票。 在制定透明和值得信赖的建议时依赖以下关键要素： • 结构性的证据摘要（如 GRADE结论摘要表）所呈现的所有对患者重要的结局的绝对利弊(166)； • 证据的质量/确定性(164)(167)； • 患者的价值观和偏好(168)； • 资源和其他考虑因素（包括可行性、适用性、公平的考量）(168)； • 每个结局的效果估计值和置信区间，以及相关证据的确定性等级（如结论摘要表所示）。如果此类数据不可得，GDG则 审查叙述性摘要(166)； • 根据GRADE的定义，建议分为有条件建议或强烈建议。如果 GDG成员对证据评估或建议的强度无法达成共识，世卫组 织将按照既定规则投票决定(165)(168)。 如果可能，我们依靠研究证据就这些关键因素展开讨论。如果没有研究证据，则根据专家意见对这些因素进行讨论，并辅以 下文概述的对GDG成员的意见调查。 利弊 GDG成员从患者的角度对 COVID-19非重症患者的结局以及COVID-19重症和危重症患者的结局进行了优先排序（评分从9分 [非常重要]到1分[不重要]不等）（见下文表1和表2）。GDG的问题采用了PICO格式（见各项建议中的证据概况）。进行优先排序 时采用的方法是先进行一项意见调查（最近一次是在2021年5月），之后由GDG讨论决定。这些优先结局被用来更新LNMA(2)。 结局的选择和结局重要性的排序 GDG成员从非重症患者（表1）以及重症和危重症患者（表2）的角度对结局进行了优先排序。 表1. GDG从非重症患者的角度对结局进行评分 结局 均值 标准差 区间 住院 8.5 0.7 7-9 死亡 8.1 1.9 3-9 生活质量 7.5 1.3 5-9 严重不良反应（如导致停药的不良事件） 7.4 1.8 3-9 症状解除时间 7.3 1.7 4-9 住院持续时间 6.6 0.9 5-8 氧气支持持续时间 6.6 1.2 5-9 有创机械通气的需要 5.9 2.3 1-8 非 SARS-CoV-2的新感染 5.6 2.1 3-9 病毒清除时间 5.5 2.4 1-9 有创机械通气持续时间 5.4 2.1 1-8 SD：标准差。 注：7-9 — 非常重要；4-6 — 重要；1-3 — 重要性有限。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 102 of 119 表2. GDG从重症和危重症患者的角度对结局进行评分 结局 均值 标准差 区间 死亡 9.0 0 9 有创机械通气的需要 8.2 0.9 6-9 有创机械通气持续时间 7.6 0.9 6-9 生活质量 6.9 1.3 5-9 住院持续时间 6.7 1.2 4-9 严重不良反应（如导致停药的不良事件） 6.7 1.8 3-9 症状解除时间 6.5 1.6 4-9 非 SARS-CoV-2的新感染 6.4 1.8 3-9 氧气支持持续时间 6.3 1.3 4-9 病毒清除时间 4.7 2.3 1-9 SD：标准差。 注：7-9 — 非常重要；4-6 — 重要；1-3 — 重要性有限。 药物治疗的绝对效果推导 对于非重症患者，我们使用了LNMA(1)(2)确定的证据所纳入的随机对照试验里对照组的中位数。对于住院，GDG定义了10% （每1000名患者100例）的基线风险阈值，它反映被考虑的治疗方法的重要绝对益处（即每1000名患者减少60例住院）。 对于重症和危重症患者，GDG认定世卫组织“团结”试验的对照组为死亡率和机械通气基线风险估计值最相关的证据来源， 该试验遍布多个国家和地域。全身性皮质类固醇现在代表了COVID-19重症和危重症患者的标准治疗（见世卫组织2020年9月发布 的强烈建议）。因此，JAK抑制剂、恢复期血浆和白介素-6受体阻滞剂证据摘要中的基线风险评估值根据皮质类固醇对死亡率和机 械通气结局的治疗效果进行了调整。死亡率采用的基线风险估计值为13%（每1000名患者130例死亡）。对于其他结局，我们使用 了形成证据时所纳入的随机对照试验里的对照组的中位数。 对每项建议都提出了关于基线风险的具体考虑。 GDG认识到基线风险以及据此计算的绝对效果可能在不同地域有很大差异，并可能随时间推移有很大改变。因此，本指南的 使用者可能更愿意使用本地事件率来估算绝对效果。 价值观和偏好 我们没有足够的信息向GDG提供关于患者经历以及做出COVID-19药物治疗的治疗决策时的价值观和偏好的循证描述。因此， GDG自行判断，在仔细权衡治疗的利弊和负担后完全知情的患者会看重什么。对价值观和偏好的判断主要来自于GDG里的 COVID-19康复患者的经历。 GDG一致认为以下价值观和偏好是完全知情的患者的典型特征： • 大多数患者不愿意使用对他们来说重要的结局上效果的证据高度不确定的药物，特别是当证据表明治疗效果小甚至没有 并且有可能造成重大危害时。 • 如果是利大于弊，且利弊的不确定性较小的情况，更多的患者会倾向于选择这种干预措施。 除了个体患者的角度，GDG也考虑了群体的角度，其中可行性、可接受性、公平和成本是重要的考虑因素。 对每项建议都提出了关于价值观和偏好以及相关的可行性和资源方面的具体考虑。 第 5步：外部和内部审查 一个外部审阅小组对指南的最终稿进行了审校，以检查是否存在事实错误，并就语言的清晰度、背景问题和对实施的影响发 表评论。技术部门收集并管理外部审阅人员的利益申报，没有发现外部审阅人员有利益冲突。但是，对于某些疗法，可能会根据 世卫组织手册（第70页）请制药公司的技术代表从行业角度对新药进行评论，因为这些个人或组织对指南草案的评论可能有助于 预期和处理争议、发现事实错误并推动所有利益攸关方的参与。审议他们对背景问题的评论时也考虑到了他们的利益。可以很容 易知晓这些人的利益冲突，因为致谢部分会说明他们的隶属关系。 本世卫组织指南随后经过了世卫组织准则审查委员会（GRC）和出版物审查委员会的审查和批准。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 103 of 119 8. 如何获取和使用本指南 这是世卫组织的一个动态指南。其所包含的建议将会更新，也会添加治疗COVID-19的其他药物的新建议。 如何获取本指南： • 世卫组织网站上的 PDF 格式(4)：此为 MAGICapp 中内容的完整版，供网络接入不稳定的人员阅读。也可以直接从 MAGICapp中下载(见右上方的齿轮图标)。 • MAGICapp上的在线多层格式：这是指南的最完整版，详细内容见下文。 • 《英国医学杂志》快速建议(5)：设计时主要考虑到临床使用者，并包括一个总结了指南中所有治疗方法的交互式信息 图。 • 世卫组织学院应用程序：供卫生工作者和公众使用的移动应用程序，带有完整的案例管理部分，可在 Apple Store 和 Google Play 上下载，其中包括一个含有指导文件、培训和工具（包括 COVID-19 疗法的最新培训模块）的完整的病例管 理章节。包括世卫组织关于 COVID-19的治疗指南和其他指南以及培训材料，供线下使用。 • 世卫组织 COVID-19 临床护理路径是一种新工具，它以简明易懂的方式总结了这些建议以供卫生工作者使用。它将本指 南与世卫组织关于 SARS-CoV-2诊断检测指南和 SARS-CoV-2感染诊断中的抗原检测指南联系起来，以利实施。 如何浏览本指南 指南在MAGICapp中编写、传播和更新，其格式和结构具有用户友好性并易于浏览(163)，可容纳证据和建议的动态更新，在 重点突出新内容的同时，酌情将现有建议保留在指南中。 在线格式和附加工具（如信息图）的目的是为了让用户在繁忙的临床实践中更容易浏览和使用指南。在线多层格式的设计旨 在使最终用户能够首先找到建议，然后再深入寻找支持性证据和其他与在实践中应用建议相关的信息，包括共同决策工具(临床接 触决策辅助工具)(163)。 图4显示了在线多层格式的设计如何使得最终用户首先查找到建议，然后深入查找与在实践中应用建议相关的支持性信息。最 终用户还需要理解什么是强烈建议/有条件建议(显示在各项建议的正下方)以及证据的确定性（研究得出的效果估计值在多大程度 上代表了治疗的真实效果）。 对于每项建议，均可通过以下选项卡获得额外信息的： • 研究证据：读者可以在此找到作为建议基础的研究证据的详细信息，如GRADE结论摘要表和叙述性证据摘要（如图 4所 示）。 • 决策证据：总结了绝对利弊和其他因素，如患者的价值观和偏好、与提供治疗相关的实践问题以及有关资源、适用性、 可行性、公平和人权的考虑。对于那些需要根据国家或地方情况调整指南的人员而言，后面这些因素尤其重要。 • 理由：解释了 GDG在制定建议时如何审议和整合决策证据的各个要素，主要集中于有争议和难度大的问题。 • 实用信息：如药物的剂量、持续用药时间和给药，或者在实践中如何通过检测识别患者。 • 决策辅助工具：临床接触中的共同决策工具。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 104 of 119 图 4. 单击获取研究证据的示例，叙述性证据摘要为 GRADE 结论摘要表补充了更多详细信息。 6.1 莫努匹拉韦（2022 年 3 月 3 日出版）2 供卫生工作者使用的其他学习模块和实施工具： • 世卫组织COVID-19基本用品预测工具（COVID-ESFT）帮助政府、合作伙伴和其他利益攸关方预测个人防护装备、诊断 检测设备、医用耗材、用于病例管理的生物医疗设备以及用于 COVID-19的支持性护理和治疗的基本药物的必要数量。 • 世卫组织严重急性呼吸道感染临床护理工具包：COVID-19改编版为在急症医院工作的临床医生提供算法和实用工具，以 管理急性呼吸道感染（包括重症肺炎、急性呼吸窘迫综合征、败血症和败血性休克）的成人和儿童患者。其中包括关于 筛查、检测、监测和治疗的信息。 • 世卫组织 Openwho.org 临床管理课程系列提供了关于 COVID-19 的完整系列课程，涵盖了从筛查和分诊到康复、检测和 治疗及姑息治疗的全面患者护理途径。 • 使用群组事件监控对低收入和中等收入国家利用莫努匹拉韦治疗轻度至中度 COVID-19 感染进行安全性监测：世卫组织 的一项研究。 本世卫组织动态指南也用于指导世卫组织药品预认证的活动。 用于非重症COVID-19患者（不包括孕妇和哺乳期妇女以及儿童） 有条件建议 对大多数人（但不是对每个人）来说利大于弊。大多数患者可能会想要这个选项。了解更多信息 我们建议对于住院风险最高的患者使用莫努匹拉韦治疗（有条件建议）。 • 在缺乏可靠的工具来预测 SARS-CoV-2感染者的住院风险的情况下，最高风险人群的典型特征包括那些未进行 COVID-19疫苗接种、年龄较大、有免 疫抑制和/或慢性疾病（如糖尿病）的人。 • 除去对那些住院风险最高的人之外，该治疗的益处在绝对意义上将是微不足道的，因此应将该治疗保留给这类人群并在疾病早期给予干预。 • 该小组确定因 COVID-19住院的风险超过 10%为阈值，大多数人在此风险水平上希望接受莫努普匹韦治疗。 • 由于缺乏临床证据，莫努匹拉韦在个体患者和人群水平上的长期危害仍然未知。这些因素包括遗传毒性、耐药性的出现和新变异株的出现（见“作用 机制”）。 • 有条件建议反映了在获得更多安全性数据之前对广泛使用莫努匹拉韦进行治疗的关切。 • 莫努匹拉韦的使用应伴随缓解策略，如避免在年轻成人中使用药物、积极的药物警戒方案以及监测病毒聚合酶和刺突序列（见“理由”）。 • 如果可用，世卫组织建议的具有不同安全性的有效替代治疗方法（如索托维单抗等中和单克隆抗体）可能是更可取的或抗病毒药物（目前正在世卫组 织评估中） · 研究证据(1) ·决策证据 ·理由 ·实践信息 ·决策辅助工具 ·反馈 帮助 摘要 莫努匹拉韦对比标准治疗 非重症COVID-19患者 8个结局 图形视图 摘要 证据摘要 莫努匹拉韦的LNMA参考了6项随机对照试验，这些试验招募了4827名门诊非重症患者； LNMA团队获得了4796名患者的数据。所有随机对照试验均已登记；没有一项发表在同行评审的 期刊上。纳入的所有研究都没有招募儿童或孕妇。附录总结了莫努匹拉韦对比标准治疗的研究特 征和偏倚风险评级、按结局分列的效果估计和相关的森林图。 对于非重症COVID-19患者，GRADE研究结果摘要表显示，对于人们感兴趣的结局，莫努匹 拉韦与标准治疗的相对和绝对效果对比，并提供了确定性评级，由LNMA提供信息[3]。 亚组分析 GDG请求进行五种预设的亚组分析： 1. 年龄：儿童（19岁及以下）与成人（20-60岁）和老年人（60岁及以上）。 2. 开始治疗时的疾病严重程度：非重症、重症、危重症。 3. 症状出现时间。 4. 血清学状态（血清阳性与血清阴性）。 5. 疫苗接种状况（未接种疫苗与已接种疫苗）。 研究没有包括儿童，也没有包括患有重症或危重症患者。所有研究均招募从出现症状起不足 5天的未接种疫苗的个体。没有报告血清学状态的数据。 新增 视图部分文本 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 105 of 119 9. 不确定性、新出现的证据和未来研究 指南关于COVID-19疗法的建议显示了所有对患者重要的结局上的治疗效果的剩余不确定性。此外，还需要更好的证据了解 COVID-19患者的预后、价值观和偏好。 在这里，我们概述了GDG确定的关于氟伏沙明和秋水仙碱的关键不确定性，用以补充之前动态指南版本中提出初始建议时所 确定的瑞德西韦、奈玛特韦-利托那韦、莫努匹拉韦、JAK抑制剂、索托维单抗、恢复期血浆、卡西瑞单抗-伊德维单抗、伊维菌 素、皮质类固醇、瑞德西韦、羟氯喹、洛匹那韦/利托那韦以及白介素-6受体阻滞剂等不确定性内容。这些不确定性可能有助于指 导今后的研究，即生成更高确定性和更相关的证据为政策和实践提供依据。我们还概述了在COVID-19快速变化的试验环境中新出 现的证据。 目前的不确定性和今后的研究机会 氟伏沙明 该小组的建议反映了该小组的看法，即目前的证据不能证明使用氟伏沙明治疗COVID-19是合理的。然而，该小组并未暗示氟 伏沙明已被证明是无效的。关于是否进一步调查氟伏沙明对COVID-19的效果，该决定可能取决于利益攸关方如何看待对氟伏沙明 （而非其他候选疗法）的效果进行调查将会产生的机会成本。该小组的讨论阐明了以下知识差距： • 氟伏沙明对有恶化风险且有明显焦虑症状的 COVID-19非重症患者有怎样的影响？ • 氟伏沙明疗法对有恶化风险的 COVID-19非重症患者有什么副作用？ • 有恶化风险的 COVID-19非重症患者中有多大比例会因药物相互作用风险而不符合治疗条件？ 小组推测，由于已有可用的有效治疗方法，研究人员未来将不得不仔细考虑氟伏沙明是否仍然可以与安慰剂或无治疗进行对 比。如果氟伏沙明的成本和可用性优势是对其进行进一步研究的理由，则可以考虑非劣效性设计。 秋水仙碱 GDG小组认为，未来的研究不太可能确定可受益于秋水仙碱的患者亚组。 瑞德西韦和奈玛特韦-利托那韦 • 准确的临床预测指南，以确定 COVID-19 非重症患者的个体患者住院风险，以便最好地识别可从这种干预措施中获益最 大的患者； • 对于需要留意的新变异株的耐药性和疗效； • 对免疫功能低下、已接种疫苗、儿童、孕妇和其他特定亚组患者的疗效 • 最佳治疗持续时间 • 与其他 COVID-19药物的联合疗法，并与其他抗病毒制剂进行头对头比较 莫努匹拉韦 • 需要临床数据来调查安全性和适用性问题(包括在儿童、哺乳期妇女或孕妇以及男性中；以及对诱发突变和致癌风险的长 期影响); • 准确的临床预测指导确定 COVID-19非重症患者的住院风险，以便最好地识别可从该干预措施中受益最大的患者; • 为个人和群体层面的关切提供数据参考，如耐药性的出现以及对新变异株的疗效; • 在非重症群体中，莫努帕拉韦与其他治疗方案(如单克隆抗体或其他抗病毒药物)的比较疗效，包括联合疗法; • 内源性细胞内相对核苷酸比率：细胞系和动物模型评估莫努匹拉韦的遗传毒性; • 在动物模型和 SARS- CoV-2感染患者中，在体外 NHC和莫努匹拉韦的选择压力下产生突变的容易程度; • 在体外、体内或人体中是否因选择压力发生突变： 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 106 of 119 • 对 NHC抗病毒活性降低; • 出现在刺突蛋白中和/或它们是否导致复制潜力/传播的增加。 • JAK抑制剂 • 联合使用巴瑞替尼和白介素-6受体阻滞剂而非单独用药对患者的增量获益; • 托法替尼和鲁索替尼对比巴瑞替尼的相对益处; • 针对儿童、孕妇和哺乳期妇女的安全性和疗效。 索托维单抗 • 准确的临床预测指南以确立 COVID -19 非重症患者的个体住院风险，从而最好地识别哪些患者将从该干预措施中受益最 大; • 对 COVID-19重症和危重症的血清阴性患者、感染新出现变异株的患者以及儿童和孕妇的疗效和安全性。 恢复期血浆 • 对重症和危重症的效果（在大多数对患者重要的结局上，证据的确定性为低至中等)； • COVID-19幸存者的长期死亡率和功能结局； • 对儿童、孕妇和哺乳期妇女的安全性和疗效； • 高滴度恢复期血浆在死亡率及其他对患者重要的结局方面的效果； • 对血清抗体检测阴性患者的效果。 卡西瑞单抗-伊德维单抗 • 准确的临床预测指南以确立 COVID-19 非重症患者的个体住院风险，从而最好地识别哪些患者将从该干预措施中获益最 大； • COVID-19非重症和重症/危重症患者的剂量和给药途径； • 对儿童和孕妇的安全性和有效性。 白介素-6受体阻滞剂 • COVID-19幸存者的长期死亡率和功能结局； • 医院感染方面的安全性数据； • 儿童、怀孕患者和免疫功能已经受损的患者的数据； • COVID-19非重症患者； • 免疫力和后续感染的风险，这可能会影响 28天后的死亡风险； • 按白介素-6受体阻滞剂的不同剂量和最佳开始用药时间分列的结局。 伊维菌素 考虑到最重要的相关结局的估计值的确定性很低，GDG认为，必须对该药进行进一步的高质量临床试验才能建议临床治疗使 用。这包括对住院和门诊患者、对不同疾病严重程度的患者以及使用不同伊维菌素剂量方案的患者做进一步的随机对照试验。这 些研究的重点应放在对患者重要的结局上，如死亡率、生活质量、是否需要住院、有创机械通气需要以及临床或症状改善时间。 此外，更好地描述伊维菌素对COVID-19患者的潜在危害也很重要。 羟氯喹 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 107 of 119 尽管仍然存在一些不确定性，但GDG认为，鉴于对不同疾病严重程度的患者和在不同地点进行的试验结果一致，进一步的研 究不太可能会发现一个在最重要的结局（死亡率、机械通气）上会从羟氯喹中获益的患者亚组。 洛匹那韦-利托那韦 尽管仍然存在一些不确定性，但GDG认为，鉴于对不同疾病严重程度的患者和在不同地点进行的试验结果一致，进一步的研 究不太可能会发现一个在最重要的结局（死亡率、机械通气）上会从洛匹那韦-利托那韦中获益的亚组患者。 皮质类固醇 • COVID-19幸存者的长期死亡率和功能结局； • COVID-19非重症患者（即没有低氧血症的肺炎）； • 当联合使用其他 COVID-19 的疗法（如新型免疫调节剂）时的结局。确定这些疗法和全身性皮质类固醇之间的相互作用 将变得越来越重要。所有用于 COVID-19 重症和危重症的研究性疗法（包括瑞德西韦）应与全身性皮质类固醇进行比 较，或比较其与全身性皮质类固醇联合使用相对于全身性皮质类固醇单独使用的疗效来进行评价； • 免疫力及后续感染的风险，这可能影响 28日后的死亡风险； • 按不同的类固醇制剂、剂量和最佳开始用药时间分列的结局。 新出现的证据 针对COVID-19干预措施的已规划和正在进行的研究数量之大前所未有——截至2022年5月共有超过5000项随机对照试验，这 意味着将有更可靠和更相关的证据出现为政策和实践提供依据(13)（见附录）。有关COVID-19治疗和预防的已登记和正在进行的 试验的概述可在传染病数据观察站通过其对COVID-19临床试验登记的动态系统综述获得(13)，也可在世卫组织网站和其他数据库 （如COVID-网络荟萃分析倡议）中获得。 尽管大多数研究规模小、方法质量参差不齐，但一些大型国际平台试验（如“康复”、“团结”和“发现”）更能够为一系 列潜在的治疗选项提供有力的证据(14)(15)(16)(17)。这种试验还可以基于新的洞见来调整其设计、招募策略和干预措施的选择，上 文概述的不确定性就是例证。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 108 of 119 10. 作者、贡献、致谢 作者、贡献、致谢 世卫组织谨此感谢所有参与人员齐心协力的工作，以确保工作过程快速、高效、可信和透明。 世卫组织疗法指导委员会（针对氟伏沙明和秋水仙碱进行了更新） 委员会包括世卫组织总部各部门和各区域的代表，并已得到世卫组织国家准备司司长和世卫组织首席科学家的批准。世卫组 织秘书处定期召开会议，根据世卫组织快速审查小组的证据更新和其他证据来源，讨论何时触发指南更新，并遴选指南制定小组 （GDG）成员参与编制动态指南。 Janet VDiaz（日内瓦突发卫生事件规划COVID-19应对临床小组负责人）、John Appiah（世卫组织非洲区域办事处病例管理负 责人）、Lisa Askie（规范和标准质量保证司）、Silvia Bertagnolio（传染病和非传染性疾病部门/COVID-19应对临床小组）、 Chiori Kodama（世卫组织东地中海区域办事处）、Krutika Kuppalli（日内瓦突发卫生事件规划COVID-19应对临床小组）、Marta Lado Castro-Rial（日内瓦突发卫生事件规划COVID-19应对临床小组）、Lorenzo Moja（卫生产品政策和标准司）、Olufemi Oladapo（性健康和生殖健康与研究司）、Dina Pfeifer（世卫组织欧洲区域办事处/突发卫生事件规划）、J Pryanka Relan（日内瓦 突发卫生事件规划COVID-19应对临床小组）、Ludovic Reveiz（泛美卫生组织卫生行动证据和情报司，COVID-19事件管理系 统）、Vaseeharan Sathiyamoorthy（科学部门卫生研究司）、Anthony Solomon（被忽视的热带病司）、Juan Soriano Ortiz（日内瓦 突发卫生事件规划COVID-19应对临床小组）、Pushpa Wijesinghe（东南亚区域办事处病例管理负责人）。提供支持的项目干事： Julie Viry和Anne Colin（日内瓦突发卫生事件规划COVID-19应对临床小组）。 世卫组织疗法指导委员会全面负责有关指导文件编制和GDG召集的决策。特别鸣谢世卫组织药物警戒团队对本次更新的支持 和贡献：Noha Iessa和Shanti Pal。 氟伏沙明建议更新的指南制定小组（GDG）构成。有关之前建议的GDG成员列表，参见此处。 Diptesh Aryal（尼泊尔Mediciti医院）；Erlina Burhan（印度尼西亚医科大学肺部和呼吸医学系感染科）；Maurizio Cecconi（意 大利米兰Humanitas研究医院）；Nerina Harley（澳大利亚墨尔本皇家墨尔本医院和爱普沃斯医疗集团）；Manai Hela（突尼斯紧急 医疗服务中心）；David S Hui（中国香港中文大学何鸿燊新发传染病中心）；Beverley Hunt（英国伦敦国王学院）；Fabian Alberto Jaimes Barragan（哥伦比亚麦德林安蒂奥基亚大学）；Sushil Kumar Kabra（印度新德里全印度医学科学研究所）；Seema Kanda （加拿大安大略省患者组成员）；Yae-Jean Kim（韩国首尔三星医疗中心成均馆大学医学院）；Niranjan Kissoon（加拿大温哥华不 列颠哥伦比亚大学儿科和急诊医学系）；Sanjeev Krishna（英国伦敦圣乔治大学）；Yee Sin Leo（新加坡国家传染病中心）； Rakesh Lodha（印度全印度医学科学研究所儿科）；Marc Mendelson（开普敦大学Groote Schuur医院传染病与艾滋病毒医学部）； Giovanni Battista Migliori（意大利Maygeri临床科学研究所肺病学系）；Emmanuel Nsutebu（阿布扎比谢赫沙赫布特医疗城）； Natalia Pshenichnaya（俄罗斯联邦莫斯科联邦消费者权益保护和公益监督局中央流行病学研究所）；Nida Qadir（美国加州大学洛 杉矶分校大卫·格芬医学院肺和危重病医学）；Andre Ricardo Araujo Da Silva（巴西弗鲁米嫩塞联邦大学母婴医学系）；Rohit Sarin （印度新德里国家结核病和呼吸道疾病研究所）；沈银忠（中国上海复旦大学上海公共卫生临床中心）；Shalini Sri Ranganathan （斯里兰卡科伦坡大学）；Miriam Stegemann（德国柏林夏里特医学院）；Ronald Swanstrom（美国北卡罗来纳大学生物化学与生 物物理系）；Tim Uyeki（美国疾病控制与预防中心流感处）。Sridhar Venkatapuram（英国伦敦国王学院）。 秋水仙碱建议更新的指南制定小组（GDG）构成。有关之前建议的指南制定小组成员列表，参见此处。 Diptesh Aryal（尼泊尔Mediciti医院）；Erlina Burhan（印度尼西亚医科大学肺部和呼吸医学系感染科）；Maurizio Cecconi（意 大利米兰Humanitas研究医院）；Nerina Harley（澳大利亚墨尔本皇家墨尔本医院和爱普沃斯医疗集团）；Manai Hela（突尼斯紧急 医疗服务中心）；David S Hui（中国香港中文大学何鸿燊新发传染病中心）；Beverley Hunt（英国伦敦国王学院）；Fabian Alberto Jaimes Barragan（哥伦比亚麦德林安蒂奥基亚大学）；Sushil Kumar Kabra（印度新德里全印度医学科学研究所）；Seema Kanda （加拿大安大略省患者组成员）；Yae-Jean Kim（韩国首尔三星医疗中心成均馆大学医学院）；Niranjan Kissoon（加拿大温哥华不 列颠哥伦比亚大学儿科和急诊医学系）；Sanjeev Krishna（英国伦敦圣乔治大学）；Yee Sin Leo（新加坡国家传染病中心）； Rakesh Lodha（印度全印度医学科学研究所儿科）；Marc Mendelson（开普敦大学Groote Schuur医院传染病与艾滋病毒医学部）； Giovanni Battista Migliori （ 意大利Maygeri临床科学研究所肺病学系）；Emmanuel Nsutebu（阿布扎比谢赫沙赫布特医疗城）； Natalia Pshenichnaya（俄罗斯联邦莫斯科联邦消费者权益保护和公益监督局中央流行病学研究所）；Nida Qadir（美国加州大学洛 杉矶分校大卫·格芬医学院肺和危重病医学）；Andre Ricardo Araujo Da Silva（巴西弗鲁米嫩塞联邦大学母婴医学系）；Rohit Sarin 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 109 of 119 （印度新德里国家结核病和呼吸道疾病研究所）；沈银忠（中国上海复旦大学上海公共卫生临床中心）；Shalini Sri Ranganathan （斯里兰卡科伦坡大学）；Miriam Stegemann（德国柏林夏里特医学院）；Ronald Swanstrom（美国北卡罗来纳大学生物化学与生 物物理系）；Tim Uyeki（美国疾病控制与预防中心流感处）。Sridhar Venkatapuram（英国伦敦国王学院）。 瑞德西韦建议更新的指南制定小组（GDG）构成。有关之前建议的指南制定小组成员列表，参见此处。 Wagdy Amin（埃及卫生和人口部）；Erlina Burhan（印度尼西亚医科大学肺部和呼吸医学系感染科）；Carolyn S Calfee（美 国旧金山加利福尼亚大学）；Maurizio Cecconi（意大利米兰Humanitas研究医院）；Duncan Chanda（赞比亚医学研究和培训研究 所）；Vu Quoc Dat（越南河内医科大学传染病学系）；Heike Geduld（南非斯泰伦博斯大学急诊医学）；Manai Hela（突尼斯紧急 医疗服务中心）；Frederique Jacquerioz Bausch（瑞士日内瓦大学医院初级保健系）；Fabian Alberto Jaimes Barragan（哥伦比亚麦 德林安蒂奥基亚大学）；Sushil Kumar Kabra（印度新德里全印度医学科学研究所）；Niranjan Kissoon（加拿大温哥华不列颠哥伦 比亚大学儿科和急诊医学系）；Sanjeev Krishna（英国伦敦圣乔治大学）；Yee Sin Leo（新加坡国家传染病中心）；Rakesh Lodha （印度全印度医学科学研究所儿科）；Natalia Pshenichnaya（俄罗斯联邦莫斯科联邦消费者权益保护和公益监督局中央流行病学研 究所）；Saniya Sabzwari（巴基斯坦卡拉奇阿迦汗大学）；Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究所）；Manu Shankar-Hari（英国伦敦国王学院）；沈银忠（中国上海复旦大学上海公共卫生临床中心）；Shalini Sri Ranganathan（斯里兰卡科 伦坡大学）；Miriam Stegemann（德国柏林夏里特医学院）；Ronald Swanstrom（美国北卡罗来纳大学生物化学与生物物理系）； Tim Uyeki（美国疾病控制与预防中心流感处）。Sridhar Venkatapuram（英国伦敦国王学院）； 奈玛特韦-利托那韦建议更新的指南制定小组（GDG）构成。有关之前建议的指南制定小组成员列表，参见此处。 Wagdy Amin（埃及卫生和人口部）；Erlina Burhan（印度尼西亚医科大学肺部和呼吸医学系感染科）；Carolyn S Calfee（美 国旧金山加利福尼亚大学）；Maurizio Cecconi（意大利米兰Humanitas研究医院）；Duncan Chanda（赞比亚医学研究和培训研究 所）；Vu Quoc Dat（越南河内医科大学传染病学系）；Stephen Freedman（加拿大卡尔加里大学卡明医学院儿科系）；Heike Geduld（南非斯泰伦博斯大学急诊医学）；Beverley Hunt（英国伦敦国王学院）；Fabian Alberto Jaimes Barragan（哥伦比亚麦德林 安蒂奥基亚大学）；Sushil Kumar Kabra（印度新德里全印度医学科学研究所）；Niranjan Kissoon（加拿大温哥华不列颠哥伦比亚 大学儿科和急诊医学系）；Sanjeev Krishna（英国伦敦圣乔治大学）；Arthur Kwizera（乌干达马凯雷雷大学健康科学学院，穆拉 戈国家转诊医院重症监护病房）；Yee Sin Leo（新加坡国家传染病中心）；Thiago Lisboa（巴西圣保罗科拉索医院）；Rakesh Lodha（印度全印度医学科学研究所儿科）；Emmanuel Nsutebu（阿布扎比谢赫沙赫布特医疗城）；Natalia Pshenichnaya（俄罗斯 联邦莫斯科联邦消费者权益保护和公益监督局中央流行病学研究所）；Saniya Sabzwari（巴基斯坦卡拉奇阿迦汗大学）；Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究所）；Manu Shankar-Hari（英国伦敦国王学院）；沈银忠（中国上海复旦大学上 海公共卫生临床中心）；Shalini Sri Ranganathan（斯里兰卡科伦坡大学）；Ronald Swanstrom（美国北卡罗来纳大学生物化学与生 物物理系）；Tim Uyeki（美国疾病控制与预防中心流感处）。Sridhar Venkatapuram（英国伦敦国王学院）； 莫努匹拉韦建议的指南制定小组（GDG）构成。有关之前建议的GDG成员列表，参见此处。 Wagdy Amin （埃及卫生与人口部）、Maurizio Cecconi（意大利米兰人道主义研究医院）、Duncan Chanda（赞比亚医学研究 和培训学院）、Vu Quoc Dat（越南河内医科大学传染病学系）、Ann De Sutter（比利时根特医学和健康科学学院）、Heike Geduld （南非斯泰伦博斯大学大学急诊医学）、Patrick Gee（美国弗吉尼亚州患者小组成员）、Matthias Gotte（加拿大阿尔伯塔大学）、 Nerina Harley（澳大利亚墨尔本皇家墨尔本医院和爱普沃斯医疗中心）、Manai Hela（突尼斯紧急医疗服务中心）、Beverley Hunt （英国伦敦国王学院）、Frederique Jacquerioz Bausch（瑞士日内瓦大学医院初级保健系）、Fabian Alberto Jaimes Barragan（哥伦 比亚安蒂奥基亚麦德林大学）、Fyezah Jehan（巴基斯坦阿迦汗大学）、Sushil Kumar Kabra（印度新德里全印度医学科学研究 所）、Yae Jean Kim（韩国首尔三星医疗中心成均馆大学医学院）、Niranjan Kissoon（加拿大温哥华英属哥伦比亚大学儿科和急诊 医学系）、Sanjeev Krishna（英国伦敦圣乔治大学）、Arthur Kwizera（乌干达穆拉戈国家转诊医院重症监护室、Makerere大学卫生 科学学院）、Yee-Sin Leo （新加坡国家传染病中心）、Thiago Lisboa（巴西圣保罗科拉索医院）、Imelda Mahaka（津巴布韦哈拉 雷津巴布韦艾滋病信托基金会）、Emmanuel Nsutebu（阿布扎比谢赫沙赫布特医疗城）、Natalia Pshenichnaya（俄罗斯联邦莫斯科 消费者权益保护和公益监督局中央流行病学研究所）、Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究所）、Manu Shankar- Hari（英国伦敦国王学院）、沈银忠（中国上海复旦大学上海公共卫生临床中心）、Shalini Sri Ranganathan （斯里兰卡科伦坡大 学）、Miriam Stegemann（德国柏林夏里特医学院）、Ronald Swanstrom（美国北卡罗莱纳大学生物化学与生物物理系）、Tim Uyeki（美国疾病控制和预防中心流感部）、Sridhar Venkatapuram（英国伦敦国王学院）、Ananda Wijewickrama（斯里兰卡卫生 部）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 110 of 119 JAK抑制剂建议的指南制定小组（GDG）构成。有关之前建议的GDG成员列表，参见此处。 Wagdy Amin（埃及卫生与人口部）、Carolyn S Calfee（加州大学旧金山分校）、Duncan Chanda（赞比亚医学研究和培训研究 所）、Vu Quoc Dat（越南河内医科大学传染病学系）、Ann De Sutter（比利时根特医学与健康科学学院）、Beverley Hunt（英国 伦敦国王学院）、Heike Geduld（南非斯泰伦博斯大学急诊医学）、Yae Jean Kim（韩国首尔三星医疗中心成均馆大学医学院）、 Sanjeev Krishna（英国伦敦圣乔治大学）、Natalia Pshenichnaya（俄罗斯联邦莫斯科联邦消费者权益保护和公益监督局中央流行病 学研究所）、Saniya Sabzwari（巴基斯坦卡拉奇阿迦汗大学）、Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究所）、沈银 忠（中国上海复旦大学上海公共卫生临床中心）、Shalini Sri Ranganathan （斯里兰卡科伦坡大学）、Miriam Stegemann（德国柏林 夏里特医学院）、Sridhar Venkatapuram（英国伦敦国王学院）、Ananda Wijewickrama（斯里兰卡卫生部）、Yee Sin Leo（新加坡 国家传染病中心）。 索托维单抗建议的指南的指南制定小组（GDG）构成。有关之前建议的GDG成员列表，参见此处。 Wagdy Amin（埃及卫生与人口部）、Fabian Alberto Jaimes Barragan（哥伦比亚安蒂奥基亚麦德林大学）、Duncan Chanda（赞 比亚医学研究和培训研究所）、Vu Quoc Dat（越南河内医科大学传染病学系）、Ann De Sutter（比利时根特医学与健康科学学 院）、Heike Geduld（南非斯泰伦博斯大学大学急诊医学）、Nerina Harley（澳大利亚墨尔本皇家墨尔本医院和爱普沃斯医疗中 心）、Beverley Hunt（伦敦国王学院，英国）、Fyezah Jehan（巴基斯坦阿迦汗大学）、Sushil Kumar Kabra（印度新德里全印度医 学科学研究所）、Yae Jean Kim（韩国首尔三星医疗中心成均馆大学医学院）、Niranjan Kissoon（加拿大温哥华英属哥伦比亚大学 儿科和急诊医学系）、Sanjeev Krishna（英国伦敦圣乔治大学）、Thiago Lisboa（巴西圣保罗科拉索医院）、Natalia Pshenichnaya （俄罗斯联邦莫斯科消费者权益保护和公益监督局中央流行病学研究所）、Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究 所）、Manu Shankar-Hari（英国伦敦国王学院）、沈银忠（中国上海复旦大学上海公共卫生临床中心）、Shalini Sri Ranganathan （斯里兰卡科伦坡大学）、Ronald Swanstrom（美国北卡罗莱纳大学）、Miriam Stegemann（德国柏林夏里特医学院）、Sridhar Venkatapuram（英国伦敦国王学院）、Yee-Sin Leo（新加坡国家传染病中心）。 恢复期血浆指南的指南制定小组（GDG）构成。有关之前建议的GDG成员列表，参见此处。 Wagdy Amin（埃及卫生与人口部）、Erlina Burhan（印度尼西亚医科大学肺和呼吸内科系感染科）、Carolyn S Calfee （加州大 学旧金山分校）、Maurizio Cecconi（意大利米兰人道主义研究医院）、Vu Quoc Dat（越南河内医科大学传染病系）、Heike Geduld （南非斯泰伦博斯大学急诊医学系）、Patrick Gee（美国患者小组成员）、Nerina Harley（澳大利亚墨尔本皇家墨尔本医院和爱普沃 斯医疗集团）、Madiha Hashimi（巴基斯坦卡拉奇齐亚乌丁大学）、Sushil Kumar Kabra（印度新德里全印医学研究所）、Seema Kanda（加拿大安大略省患者小组成员）、Leticia Kawano-Dourado（巴西圣保罗科拉索医院研究所）、Niranjan Kissoon（加拿大温 哥华英属哥伦比亚大学儿科和急诊医学系）、Greta Mino（厄瓜多尔瓜亚基尔的阿尔西瓦尔医院）、Natalia Pshenichnaya（俄罗斯联 邦莫斯科消费者权益保护局中央流行病学研究所）、Nida Qadir（美国加州大学洛杉矶分校戴维·格芬医学院肺部和危重症医学 系）、Saniya Sabzwari（巴基斯坦卡拉奇的阿迦汗大学）、Rohit Sarin（印度新德里国家结核病和呼吸道疾病研究所）、沈银忠（中 国上海复旦大学上海公共卫生临床中心）、Shalini Sri Ranganathan（斯里兰卡科伦坡大学）、Miriam Stegeman（德国柏林夏里特医 科大学）、Sridhar Venkatapuam（伦敦国王学院）、Ananda Wuewickrama（斯里兰卡卫生部）。 方法主席 Gordon Guyatt（卡西瑞单抗-伊德维单抗、JAK抑制剂、奈玛特韦-利托那韦）、Bram Rochwerg（白介素-6受体阻滞剂、伊维 菌素、瑞德西韦、洛匹那韦-利托那韦、恢复期血浆、莫努匹拉韦、瑞德西韦更新）、Reed Siemieniuk（羟氯喹）、Francois Lamontagne（皮质类固醇、索托维单抗、秋水仙碱、氟伏沙明、氟伏沙明、秋水仙碱）。 临床主席 Michael Jacobs（卡西瑞单抗-伊德维单抗、白介素-6受体阻滞剂、伊维菌素、瑞德西韦、羟氯喹、洛匹那韦-利托那韦、JAK抑 制剂、瑞德西韦更新），Yee-Sin Leo（皮质类固醇），Leticia Kawano-Dourado（恢复期血浆、索托维单抗、莫努匹拉韦），Miriam Stegemann（氟伏沙明、秋水仙碱）。 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 111 of 119 方法资源专家 Arnav Agarwal（加拿大多伦多大学）、Thomas Agoritsas（瑞士日内瓦大学医院）、Romina Brignardello-Peterson（加拿大麦克 马斯特大学）、Gordon H Guyatt（加拿大麦克马斯特大学）、George Tomlinson（加拿大多伦多健康网络大学医学系）、Per Olav Vandvik（神奇证据生态系统基金会，挪威奥斯陆大学）、曾力楠（中国成都四川大学华西第二医院；加拿大麦克马斯特大学）。 指南支持协作委员会 该委员会在世卫组织和神奇证据生态系统基金会（MAGIC）之间进行协调，以使世卫组织的指南得以快速制定并传播到各个 发布平台：Thomas Agoritsas（神奇证据生态系统基金会，日内瓦大学医院）、Janet Diaz（世界卫生组织）、Helen Mcdonald （《英国医学杂志》）、Gordon Guyatt（加拿大麦克马斯特大学）、Per OlavVandvik（神奇证据生态系统基金会，奥斯陆大 学）、Julie Viry（世界卫生组织）。 临时顾问： 特别感谢Andrew Owen教授（利物浦大学分子和临床药理学系）对伊维菌素、白介素-6受体阻滞剂、卡西瑞单抗-伊德维单 抗、恢复期血浆、单克隆抗体、JAK抑制剂、索托维单抗、莫努匹拉韦、奈玛特韦-利托那韦、瑞德西韦更新、氟伏沙明、秋水仙 碱）的药代动力学分析所作的贡献。 特别感谢Craig Thompson教授（牛津大学）在与卡西瑞单抗-伊德维单抗指南相关的诊断性检测方面所做的贡献。 外部审阅人员 特别感谢外部审阅人员对恢复期血浆、卡西瑞单抗-伊德维单抗、白介素-6受体阻滞剂、伊维菌素、索托维单抗、莫努匹拉 韦、奈玛特韦-利托那韦、瑞德西韦、氟伏沙明和秋水仙碱提供真知灼见： Aula Abbara（无国界医生组织）、Yaseen Arabi（沙特国王沙特·本·阿卜杜勒·阿齐兹国王卫生学大学）、Marcio da Fonseca （无国界医生组织）、Richard Kojan（国际医疗行动联盟）、Carolina Nanclares（无国界医生组织）和Saschveen Singh（无国界医 生组织）。 特别感谢Paula Dakin（再生元制药公司）应邀对卡西瑞单抗-伊德维单抗（第六版）进行评论以发现事实错误，并就语言的清 晰度、背景问题和对实施的影响发表评论。也从再生元制药公司的利益角度对其评论给予了考虑。 特别感谢Lisa Burry（多伦多蒙特西奈医院药剂科）作为临床药剂师对实用信息表（索托维单抗、莫努匹拉韦、奈玛特韦-利 托那韦、瑞德西韦更新）的贡献。 特别感谢Chistine Tsang（英国牛津大学医院NHS基金会信托)作为临床药剂师对实用信息表的贡献（莫努匹拉韦、奈玛特韦- 利托那韦、瑞德西韦的更新）。 观察员 Sade Ogunsala（秋水仙碱和氟伏沙明）。 信息图 特别感谢《英国医学杂志》为本指南提供了信息图。 供资 非常感谢比尔及梅琳达·盖茨基金会、挪威公共卫生局和德国。 特别感谢神奇证据生态系统基金会无偿提供方法论的支持。 荟萃分析团队 特别感谢麦克马斯特大学 LNMA团队 Arnav Agarwal（加拿大多伦多大学）、Thomas Agoritsas（神奇证据生态系统基金会、瑞士日内瓦大学医院）、Jessica J Bartoszko（加拿大麦克马斯特大学）、Romina Brignardello-Petersen、Derek K Chu（加拿大麦克马斯特大学）、Rachel Couban（加 拿大麦克马斯特大学）、Andrea Darzi（加拿大麦克马斯特大学）、Tahira Devji（加拿大麦克马斯特大学）、薄芳（中国重庆医科 大学）、Carmen Fang（加拿大多伦多威廉·奥斯勒健康网络）、Signe Agnes Flottorp（挪威奥斯陆大学卫生与社会研究所）、Farid Foroutan（加拿大麦克马斯特大学）、Long Ge（中国甘肃兰州大学公共卫生学院）、Gordon H Guyatt（加拿大麦克马斯特大 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 112 of 119 学）、Mi Ah Han（韩国光州朝鲜大学医学院）、Diane Heels-Ansdell（加拿大麦克马斯特大学）、Kimia Honarmand（加拿大伦敦 韦士敦大学医学系）、Liangying Hou（中国甘肃兰州大学公共卫生学院）、侯筱蓉（中国重庆医科大学）、Quazi Ibrahim（加拿 大麦克马斯特大学）、Ariel Izcovich（阿根廷布宜诺斯艾利斯阿勒曼医院临床医学服务处）、Elena Kum（加拿大麦克马斯特大 学）、Francois Lamontagne（加拿大舍布鲁克大学、Qin Liu（中国重庆医科大学公共卫生管理学院）、Mark Loeb（加拿大麦克马 斯特大学）、Maura Marcucci（加拿大麦克马斯特大学）、Shelley L McLeod（加拿大多伦多西奈医院施瓦茨-雷斯曼急诊医学研究 所）、Sharhzad Motaghi,（加拿大麦克马斯特大学）、Srinivas Murthy（加拿大英属哥伦比亚大学）、Reem A Mustafa（加拿大麦 克马斯特大学）、John D Neary（加拿大麦克马斯特大学）、Hector Pardo-Hernandez（西班牙圣保罗生物医学研究所）、Anila Qasim（加拿大麦克马斯特大学）、Gabriel Rada（智利Epistemonikos基金会）、Irbaz Bin Riaz（美国罗切斯特梅奥诊所）、Bram Rochwerg（加拿大麦克马斯特大学）、Behnam Sadeghirad（加拿大麦克马斯特大学）、Nigar Sekercioglu（加拿大麦克马斯特大 学）、Lulu Sheng（中国重庆医科大学）、Reed AC Siemieniuk（加拿大麦克马斯特大学）、Ashwini Sreekanta（加拿大麦克马斯特 大学）、Charlotte Switzer（加拿大麦克马斯特大学）、Britta Tendal（澳大利亚蒙纳士大学）、Lehana Thabane（加拿大麦克马斯 特大学）、George Tomlinson（加拿大多伦多大学、Tari Turner（澳大利亚蒙纳士大学）、Per Olav Vandvik（神奇证据生态系统基 金会，挪威奥斯陆大学）、Robin WM Vernooij（荷兰乌得勒支大学医学中心）、Andrés Viteri-García（智利圣地亚哥Epistemonikos 基金会）、Ying Wang（加拿大麦克马斯特大学）、Liang Yao（加拿大麦克马斯特大学）、Zhikang Ye（加拿大麦克马斯特大 学）、Dena Zeraatkar（加拿大麦克马斯特大学(1)(2)(3)。 特别感谢世卫组织COVID-19疗法快速证据评估（REACT）工作组发表的文章：COVID-19住院患者中白细胞介素-6拮抗剂给 药与死亡率和其他结局的关联：前瞻性荟萃分析(116)。 Manu Shankar-Hari、Claire L Vale、Peter J Godolphin、David Fisher、Julian PT Higgins、Francesca Spiga、Jelena Savović、Jayne Tierney、Nor ArisahMisnan、Gabriel Baron、Julie S Benbenishty、Lindsay R Berry、Niklas Broman、Alexandre Biasi Cavalcanti、Roos Colman、Stefanie L De Buyser、Lennie PG Derde、Pere Domingo、Sharifah Faridah Syed Omar、Ana Fernandez-Cruz、Thijs Feuth、 Felipe Garcia、Rosario Garcia-Vicuna、Isidoro Gonzalez-Alvaro、Anthony C Gordon、Richard Haynes、Olivier Hermine、Peter W Horby、Nora K Horick、Kuldeep Kumar、Bart N Lambrecht、Martin J Landray、Lorna Leal、David J Lederer、Elizabeth Lorenzi、 Xavier Mariette、Nicolas Merchante、Nor ArisahMisnan、Shalini V Mohan、Michael C Nivens、Jarmo Oksi、Jose A Perez-Molina、 Reuven Pizov、Raphael Porcher、Simone Postma、Reena Rajasuriar、Athimalaipet V Ramanan、Pankti D Reid、Abraham Rutgers、 Aranzazu Sancho-Lopez、Todd B Seto、Sumathi Sivapalasingam、Arvinder Singh Soin、Natalie Staplin、John H Stone、Garth W Strohbehn、Jonas Sunden-Cullberg、Julian Torre-Cisneros、Larry W Tsai、Hubert van Hoogstraten、Tom van Meerten、Viviane Cordeiro Veiga、Peter Westerwheel、Srinivas Murthy、Janet V Diaz、John C Marshall、Jonathan A C Sterne。 我们要在此感谢雷迪博士实验室和默沙东（在美国和加拿大称为默克）以及Ridgeback Biotherapeutics分享发表前数据，这些 数据被用来进行荟萃分析，为第九版世卫组织动态指南更新提供参考。 113 of 119 疗法与2019冠状病毒病：动态指南—世界卫生组织（世卫组织） 参考文献 1. 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Лекарственная терапия при COVID-19 ВАРИАТИВНЫЕ РЕКОМЕНДАЦИИ 14 июля 2022 г. WHO/2019-nCoV/therapeutics/2022.4 © Всемирная организация здравоохранения 2022 Некоторые права защищены. Данная публикация распространяется на условиях лицензии Creative Commons «С указанием авторства – Некоммерческая – Распространение на тех же условиях» 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by- nc-sa/3.0/igo/deed.ru). Лицензией допускается копирование, распространение и адаптация публикации в некоммерческих целях с указанием библиографической ссылки согласно нижеприведенному образцу. Никакое использование публикации не означает одобрения ВОЗ какой-либо организации, товара или услуги. Использование логотипа ВОЗ не допускается. Распространение адаптированных вариантов публикации допускается на условиях указанной или эквивалентной лицензии Creative Commons. При переводе публикации на другие языки приводится библиографическая ссылка согласно нижеприведенному образцу и следующая оговорка: «Настоящий перевод не был выполнен Всемирной организацией здравоохранения (ВОЗ). ВОЗ не несет ответственности за его содержание и точность. Аутентичным подлинным текстом является оригинальное издание на английском языке». Урегулирование споров, связанных с условиями лицензии, производится в соответствии с согласительным регламентом Всемирной организации интеллектуальной собственности (http://www.wipo.int/amc/en/mediation/rules/). Образец библиографической ссылки. Лекарственная терапия при COVID-19: Вариативные Рекомендации, 14 июля 2022 г. [Therapeutics and COVID-19: living guideline, 14 July 2022]. Женева: Всемирная организация здравоохранения; 2022 (WHO/2019- nCoV/therapeutics/2022.4). Лицензия: CC BY-NC-SA 3.0 IGO. Данные каталогизации перед публикацией (CIP). Данные CIP доступны по ссылке: http://apps.who.int/iris/. 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ВОЗ не несет никакой ответственности за ущерб, связанный с использованием материалов. Контактные данные: Сеть ВОЗ по клинической оценке и реагированию на новые инфекционные заболевания EDCARN@who.int ВОЗ продолжает внимательно следить за ситуацией на предмет любых изменений, которые могут повлиять на эти временные рекомендации. В случае возникновения таких изменений ВОЗ выпустит следующую обновленную версию. В противном случае срок действия настоящих временных рекомендаций истекает через 2 года после даты публикации. 3 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Разделы 1. Резюме рекомендаций .................................................................................................................................................................................. 4 2. Список сокращений ....................................................................................................................................................................................... 6 3. Введение ........................................................................................................................................................................................................ 7 4. Причины опубликования данной версии рекомендаций и перспективы на будущее ............................................................................. 8 5. Разъяснение и применение определений ВОЗ, касающихся тяжести течения заболевания ................................................................ 9 6. Рекомендации в отношении лекарственных средств .............................................................................................................................. 10 6.1. Обзор лекарственных средств, рекомендаций и основных вопросов для рассмотрения в ходе их применения ...................... 10 6.2. Флувоксамин (опубликовано 14 июля 2022 г.) ................................................................................................................................. 12 6.2.1. Механизм действия .................................................................................................................................................................. 17 6.3. Колхицин (опубликовано 14 июля 2022 г.)........................................................................................................................................ 18 6.3.1. Механизм действия .................................................................................................................................................................. 21 6.4. Комбинация нирматрелвира и ритонавира (опубликовано 22 апреля 2022 г.) ............................................................................. 22 6.4.1. Механизм действия .................................................................................................................................................................. 35 6.5. Ремдесивир (опубликовано 22 апреля 2022 г.) ................................................................................................................................ 36 6.5.1. Механизм действия .................................................................................................................................................................. 43 6.6. Молнупиравир (опубликовано 3 марта 2022 г.) ............................................................................................................................... 44 6.6.1. Механизм действия .................................................................................................................................................................. 49 6.7. Ингибиторы янус-киназ (опубликовано 14 января 2022 г.) ............................................................................................................. 51 6.7.1. Механизм действия .................................................................................................................................................................. 62 6.8. Сотровимаб (опубликовано 14 января 2022 г.) ................................................................................................................................ 63 6.8.1. Механизм действия .................................................................................................................................................................. 68 6.9. Плазма реконвалесцентов (опубликовано 7 декабря 2021 г.) ........................................................................................................ 69 6.9.1. Механизм действия .................................................................................................................................................................. 76 6.10. Комбинация казиривимаба и имдевимаба (нейтрализующие моноклональные антитела) (опубликовано 24 сентября 2021 г.) .................................................................................................................................................. 78 6.10.1. Механизм действия .................................................................................................................................................................. 89 6.11. Блокаторы рецепторов к IL-6 (опубликовано 6 июля 2021 г.) ......................................................................................................... 90 6.11.1. Механизм действия .................................................................................................................................................................. 96 6.12. Ивермектин (опубликовано 31 марта 2021 г.) .................................................................................................................................. 97 6.12.1. Механизм действия ................................................................................................................................................................ 102 6.13. Гидроксихлорохин (опубликовано 17 декабря 2020 г.) .................................................................................................................. 103 6.14. Комбинация лопинавира и ритонавира (опубликовано 17 декабря 2020 г.)................................................................................ 108 6.15. Системные кортикостероиды (опубликовано 2 сентября 2020 г.) ................................................................................................ 112 7. Методы: каким образом велась разработка этого рекомендательного документа ............................................................................. 121 8. Как получить доступ и пользоваться этим рекомендательным документом? ..................................................................................... 125 9. Малоизученные вопросы, новые фактические данные и последующие научные исследования ...................................................... 127 10. Авторство, вклад, выражение признательности..................................................................................................................................... 130 Библиография .................................................................................................................................................................................................. 135 4 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Резюме рекомендаций Клиническая проблема. Какова роль лекарственных средств в лечении пациентов с COVID-19? Описание ситуации. Доказательная база в отношении средств лечения COVID-19 быстро расширяется, и в настоящее время проводится либо уже завершено большое количество рандомизированных клинических исследований (РКИ). В данное обновленное издание были включены новые рекомендации, касающиеся применения флувоксамина и колхицина у пациентов с нетяжелым течением COVID-19; в первом случае в основу были положены данные систематического обзора трех РКИ с участием 2196 пациентов, во втором случае – 13 РКИ с участием 18 172 пациентов. Новые рекомендации. Группа по разработке руководящих принципов рекомендует не применять флувоксамин у пациентов с нетяжелым течением заболевания за исключением ситуации клинических исследований. Сделана настоятельная рекомендация не применять колхицин у пациентов с нетяжелым течением заболевания. В отношении пациентов с тяжелой или крайне тяжелой формой заболевания рекомендаций сделано не было ввиду малого объема либо полного отсутствия данных, касающихся использования указанных препаратов в данной группе населения. Для лечения пациентов с нетяжелым течением COVID-19, относящихся к группе наивысшего риска госпитализации, имеется ряд альтернатив. В связи с тем, что прямое сравнение в рамках испытаний не проводилось, для обоснования выбора препаратов со сходным механизмом действия применялись косвенные сравнительные данные сетевого метаанализа (СМА; см. описание методов в разделе 7). Выбор определяется доступностью препаратов, путем их введения (ремдесивир вводят только внутривенно), совместным применением других лекарственных средств, длительностью лечения, а также продолжительностью времени, прошедшего от момента появления симптомов до начала лечения в рамках исследований. Разъяснение новых рекомендаций. При анализе фактических сведений, которые легли в основу рекомендаций, группа по разработке руководящих принципов рассмотрела в совокупности данные, отражающие относительную пользу и отрицательные эффекты рассматриваемого вмешательства, ценностные ориентиры и предпочтения заинтересованных сторон, а также вопросы практического осуществления. При вынесении рекомендации не использовать флувоксамин для лечения пациентов с нетяжелым течением заболевания за исключением условий клинических исследований группа по разработке руководящих принципов признала отсутствие четкого механизма действия, которым могла бы объясняться эффективность препарата, а также низкую и среднюю степень убедительности доказательных данных, свидетельствующих в пользу слабого или нулевого эффекта в отношении госпитализации, перевода на искусственную вентиляцию легких, а также смертности. Кроме того, группа подчеркнула отсутствие достоверных данных, касающихся наблюдаемых на фоне терапии серьезных побочных явлений, выявленных значимых лекарственных взаимодействий, а также значительной доли случаев отказа от применения препаратов в рассмотренных исследованиях. Согласно прогнозам группы, важных различий в ценностных ориентирах и предпочтениях, касающихся применения флувоксамина, выявлено не будет, в связи с чем была сделана рекомендация не использовать данный препарат за исключением случаев клинических испытаний. При вынесении рекомендации не использовать колхицин для лечения пациентов с нетяжелым течением заболевания группа подчеркнула наличие фактических данных, указывающих на незначительный или нулевой эффект в отношении госпитализации, перевода на искусственную вентиляцию легких, а также смертности (средняя степень убедительности). Кроме того, группа по разработке руководящих принципов обсудила достоверно установленные риски лекарственных взаимодействий, а также проблему узкого терапевтического окна колхицина, особенно при назначении пациентам с печеночной или почечной недостаточностью либо с риском данных патологий. Колхицин может обладать выраженной токсичностью, в отдельных случаях приводящей к летальным исходам. Ранее были вынесены следующие рекомендации Рекомендовано для пациентов с тяжелым и крайне тяжелым течением COVID-19: • настоятельная рекомендация в пользу применения системных кортикостероидов; • настоятельная рекомендация в пользу применения блокаторов рецепторов к IL-6 (тоцилизумаб или сарилумаб) в комбинации с кортикостероидами; • настоятельная рекомендация в пользу применения барицитиниба в качестве альтернативы блокаторам рецепторов к IL-6 в комбинации с кортикостероидами. • условная рекомендация в пользу применения комбинации казиривимаба и имдевимаба у пациентов с серонегативным статусом при условии доступности оперативного генотипирования вируса с подтверждением заражения чувствительным к данным препаратам вариантом вируса SARS-CoV-2. Рекомендовано для пациентов с нетяжелым течением COVID-19, относящихся к группе наивысшего риска госпитализации: • настоятельная рекомендация в пользу применения комбинации лопинавира и ритонавира; • условная рекомендация в пользу применения молнупиравира; • условная рекомендация в пользу применения сотровимаба; • условная рекомендация в пользу применения комбинации казиривимаба и имдевимаба при условии доступности оперативного генотипирования вируса с подтверждением заражения чувствительным к данным препаратам вариантом вируса SARS-CoV-2; • условная рекомендация в пользу применения ремдесивира. 5 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Не рекомендовано для пациентов с нетяжелым течением COVID-19: • условная рекомендация не применять системные кортикостероиды; • настоятельная рекомендация не применять плазму доноров-реконвалесцентов. Не рекомендовано для пациентов с нетяжелым течением COVID-19, относящихся к группе низкого риска госпитализации: • условная рекомендация не применять комбинацию нирматрелвира и ритонавира. Не рекомендуется для пациентов с тяжелым и крайне тяжелым течением COVID-19: • рекомендация не применять плазму реконвалесцентов, за исключением случаев клинических испытаний; • условная рекомендация не применять руксолитиниб и тофацитиниб. Не рекомендуется, независимо от степени тяжести заболевания COVID-19: • настоятельная рекомендация не применять гидроксихлорохин; • настоятельная рекомендация не применять комбинацию лопинавира и ритонавира; • рекомендация не применять ивермектин за исключением случаев клинических испытаний. Сведения о настоящих рекомендациях. В этой версии вариативных рекомендаций Всемирной организации здравоохранения (ВОЗ) представлены новые рекомендации в отношении флувоксамина и колхицина для лечения пациентов с нетяжелым течением COVID-19. Как правило, группа по разработке руководящих принципов проводит оценку лекарственного средства в тех случаях, когда, по мнению ВОЗ, накопленный объем фактических данных достаточен для вынесения рекомендации. Хотя при подготовке рекомендаций экспертная группа в первую очередь рассматривает проблему с точки зрения отдельного пациента, ею также учитываются вопросы ресурсной оснащенности, приемлемости, практической осуществимости, обеспечения равноправного доступа к услугам здравоохранения и соблюдения прав человека. Данный рекомендательный документ был составлен в соответствии со стандартами и методами подготовки качественных рекомендаций. Документ подготовлен с учетом ОДСМА (1)(2)(3). Обновления и доступ к рекомендациям. Настоящий документ представляет собой одиннадцатую версию (десятое обновленное издание) вариативных рекомендаций. Она заменяет выпущенные ранее версии (2 сентября 2020 г., 20 ноября 2020 г., 17 декабря 2020 г., 31 марта 2021 г., 6 июля 2021 г., 24 сентября 2021 г., 7 декабря 2021 г., 14 января 2022 г., 3 марта 2022 г. и 22 апреля 2022 г.). Как текущая, так и предыдущие версии рекомендаций размещены на веб- сайте ВОЗ (4), на веб-сайте журнала BMJ (5), а также в приложении MAGICapp (в онлайновом формате и в формате PDF для читателей с ограниченным доступом к сети Интернет). Формат и структура данных рекомендаций, размещение, распространение и обновление которых происходит на базе онлайновой платформы (MAGICapp), обеспечивают для пользователей удобство работы и поиска и позволяют знакомиться с новыми аспектами, относящимися к актуальным положениям рекомендательного документа, по мере поступления новых фактических сведений и рекомендаций. Данные вариативные рекомендации ВОЗ по лечению COVID-19 согласованы с более комплексным руководящим документом «Клиническое ведение случаев COVID-19» (6). Рекомендации в отношении лекарственных средств для профилактики (не лечения) COVID-19, основанные на ОДСМА (9), представлены в качестве отдельного документа на веб-сайте ВОЗ (7) и в журнале BMJ (8). 6 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 2. Список сокращений АЛТ аланинаминотрансфераза ОРДС острый респираторный дистресс-синдром CAP внебольничная пневмония ДИ доверительный интервал COVID-19 коронавирусная инфекция 2019 г. DOI декларация интересов рСКФ расчетная скорость клубочковой фильтрации FDA Управление по контролю за пищевыми продуктами и лекарствами США GDG группа по разработке руководящих принципов ЖК желудочно-кишечный GRADE методология GRADE: система градации качества анализа, разработки и оценки рекомендаций GRC Комитет по обзору руководящих принципов IL-6 интерлейкин-6 ИИВЛ инвазивная искусственная вентиляция легких JAK янус-киназа ОДСМА обновленные данные сетевого метаанализа СНСД страны с низким и средним уровнем дохода MAGIC организация "Magic Evidence Ecosystem Foundation" СР средняя разность OIS оптимальный объем информации ОШ отношение шансов PICO популяция, вмешательство, сравнение, исход ПМА проспективный метаанализ РКИ рандомизированное контролируемое клиническое испытание ОР относительный риск / отношение рисков SAE серьезное побочное явление СИОЗС селективные ингибиторы обратного захвата серотонина TACO циркуляторная перегрузка, вызванная трансфузией (TACO-синдром) TRALI острое посттрансфузионное повреждение легких (TRALI-синдром) ВОЗ Всемирная организация здравоохранения 7 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 3. Введение Справочная информация По состоянию на май 2022 г. во всем мире было зарегистрировано свыше 524 миллионов подтвержденных случаев COVID-19 (10). Пандемия унесла свыше 6,2 миллиона жизней (10). В целом ряде стран с высоким уровнем дохода вакцинация существенным образом влияет на количество заболевших и показатели госпитализации, вместе с тем последствием ограничений глобального доступа к вакцинам является уязвимость многих групп населения (10)(11). По-прежнему сохраняется неопределенность в отношении длительности защиты и эффективности существующих вакцин (а также эффективности существующих вариантов лечения COVID-19) против новых вариантов вируса SARS-CoV-2 даже у вакцинированных лиц. С учетом вышеизложенного, потребность в нахождении более эффективных вариантов лечения COVID-19 остается актуальной. В ходе пандемии COVID-19 и на фоне стремительного роста как исследовательской активности, так и появления недостоверной информации, стало очевидным, что для получения корректных выводов на основе поступающих данных, а также для разработки четких клинических рекомендаций необходимы достоверные, доступные и регулярно обновляемые вариативные рекомендации (12). В данных руководящих указаниях учтены сведения, поступающие из РКИ в отношении существующих и новых методов лекарственного лечения COVID-19. К настоящему моменту зарегистрировано, проводится или завершено свыше 5000 испытаний по проблеме COVID-19 (см. раздел 9, посвященный новым данным, а также тематическое приложение) (13). К их числу относятся крупные исследования, проходящие на национальных или международных платформах (например, ACCT, RECOVERY, WHO SOLIDARITY, REMAP-CAP и ACTIV), в которые ведется набор большого количества пациентов в различных странах, и дизайн которых обеспечивает практическую ориентированность и гибкость (14)(15)(16)(17). Обзор проходящих в настоящее время испытаний размещен Обсерваторией данных по инфекционным болезням в разделе текущих систематических обзоров зарегистрированных клинических испытаний средств для лечения COVID-19 (13), а также на веб‑сайте ВОЗ. Ряд ОДСМА, относящихся к этому рекомендательному документу, содержит данные новых исследований и обеспечивает возможность анализа сравнительной эффективности широкого спектра средств лечения COVID-19. Кроме того, для обоснования данных вариативных рекомендаций использованы дополнительные фактические сведения, относящиеся к безопасности, прогнозу, а также ценностным ориентирам и предпочтениям пациентов в отношении средств лечения COVID-19. По актуальным данным текущего систематического обзора 232 предиктивных моделей COVID-19 у госпитализированных пациентов было выявлено два перспективных инструмента прогнозирования риска для обоснования рекомендаций, содержащихся в настоящей одиннадцатой версии документа; к ним относятся диагностическая модель Jehi, а также модель смертности 4C (подробнее см. раздел 6.1) (18). 8 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 4. Причины опубликования данной версии рекомендаций и перспективы на будущее Этот документ является одиннадцатой версией вариативных рекомендаций ВОЗ и касается применения флувоксамина и колхицина у пациентов с нетяжелым течением COVID-19. В нем рассматриваются данные трех и семи РКИ соответственно, включенных в обновление ОДСМА и касающихся лекарственных средств для лечения COVID-19 (1). На рисунке 1 представлены другие изучаемые лекарственные средства, подлежащие оценке в рамках подготовки вариативных рекомендаций ВОЗ, сведения о которых также размещены на портале ВОЗ (4). Каждой точке соответствует одна неделя. При принятии решения о том, какие лекарственные средства следует охватить в рекомендациях, ВОЗ учитывает разнообразные факторы, в том числе объем имеющейся доказательной базы для обоснования рекомендаций, а также определяет вероятность и сроки появления дополнительных фактических данных. В составе ВОЗ действует постоянный Руководящий комитет (см. раздел 10), ведающий вопросами оценки новых лекарственных средств и обновления существующих рекомендаций. Рисунок 1. Средства для лечения COVID-19, находящиеся на стадии оценки 9 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 5. Разъяснение и применение определений ВОЗ, касающихся тяжести течения заболевания Справочная информация Действие данных рекомендаций распространяется на всех пациентов с COVID‑19. Рекомендации могут отличаться в зависимости от тяжести течения COVID-19 в соответствии с определениями ВОЗ тяжести заболевания (см. ниже) (6). Данные определения позволяют не учитывать возможность доступа к медицинской помощи при разделении пациентов на подгруппы. Определения ВОЗ тяжести течения COVID-19 • Крайне тяжелое течение COVID-19 – устанавливается на основании наличия критериев острого респираторного дистресс‑синдрома (ОРДС), сепсиса, септического шока или других патологических состояний, которые, как правило, требуют проведения лечебных мероприятий по поддержанию жизненно важных функций организма, например искусственной вентиляции легких (инвазивной или неинвазивной) либо введения вазопрессоров. • Тяжелое течение COVID-19 – определяется наличием любого из следующих критериев: • насыщение крови кислородом < 90% при дыхании атмосферным воздухом; • признаки пневмонии; • признаки тяжелой дыхательной недостаточности (у взрослых – использование вспомогательной дыхательной мускулатуры, невозможность произнесения полных предложений, частота дыхательных движений > 30 в минуту, у детей – крайне выраженное втяжение нижней части грудной клетки, «кряхтящее» дыхание, центральный цианоз либо наличие других признаков, указывающих на опасное для жизни состояние, в том числе ребенок не берет грудь или не может пить, наблюдается психическая заторможенность или снижение уровня сознания либо появление судорог в сочетании с признаками пневмонии). • Нетяжелое течение COVID-19 – определяется как отсутствие каких‑либо из признаков тяжелого или крайне тяжелого течения COVID‑19. Внимание. Группа по разработке руководящих принципов подчеркивает, что пороговое значение насыщения крови кислородом 90%, применяемое для установления тяжелого течения COVID-19, выбрано произвольно, и при выявлении пациентов, нуждающихся в системной терапии кортикостероидами, к его интерпретации необходимо подходить с осторожностью. Например, принимая решение о том, является ли низкое насыщение крови кислородом признаком тяжести заболевания либо нормой для определенного пациента, страдающего хроническим заболеванием легких, клиницист должен опираться на собственное профессиональное суждение. Аналогичным образом клиницист может интерпретировать насыщение крови кислородом в диапазоне 90–94% при дыхании атмосферным воздухом как признак патологии у пациента со здоровыми легкими и рассматривать это как ранний признак тяжелого течения заболевания в случае, если состояние пациента ухудшается. В общем случае группа рекомендует при наличии сомнений трактовать все спорные наблюдения в пользу более тяжелого течения заболевания. Инфографика отражает эти три группы, выделенные по признаку тяжести заболевания, а также основные характеристики для учета в практической работе. Инфографика: совместное производство BMJ и MAGIC; дизайн: Will Stahl-Timmins (см. BMJ Rapid Recommendations). 10 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6. Рекомендации в отношении лекарственных средств Схема принятия решений 6.1. Обзор лекарственных средств, рекомендаций и основных вопросов для рассмотрения в ходе их применения Справочная информация Обновлено Инфографика отражает резюме рекомендаций ВОЗ в разбивке по критериям тяжести заболевания. Кроме того, при практическом применении рекомендаций клиницисты должны принимать в расчет важные аспекты, перечисленные ниже. Выбор предпочтительного лекарственного средства Как для пациентов с нетяжелой формой COVID-19, так и для пациентов с тяжелой формой инфекции доступен ряд альтернативных вариантов лечения. Выбор определяется доступностью препаратов, путем их введения (ремдесивир и моноклональные антитела вводят только внутривенно), совместным применением других лекарственных средств, длительностью лечения, а также продолжительностью времени, прошедшего от момента появления симптомов до начала лечения в рамках исследований. Ряд средств используется в комбинациях (например, как в случае тяжелого или крайне тяжелого течения COVID-19), тогда как другие применяются в качестве альтернативы. Рекомендованные комбинации лекарственных средств основаны на прямых сравнениях в ходе исследований, доказавших дополнительные преимущества, например комбинация барицитиниба или блокаторов рецепторов к интерлейкину-6 с системными кортикостероидами у пациентов с тяжелым и крайне тяжелым течением COVID-19. Для обоснования предпочтительного использования того или иного препарата со сходным механизмом действия в отсутствие прямых сравнений различных вариантов лечения в исследованиях применялись косвенные сравнения по данным ОДСМА (см. раздел 7 «Методы»). Польза и вред, связанные с применением альтернативных вариантов лечения, разъяснены в интерактивном инструменте содействия принятию решений, который также может быть использован при совместном принятии решений. Эффективность может быть различной в зависимости от конкретных вариантов вируса SARS-CoV-2. Например, эффективность ранее рекомендованных антител может быть ниже при заражении вариантом BA.1/BA.2 «омикрон». Выявление пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации Ряд рекомендаций, касающихся лекарственных средств, распространяется только на лиц с наивысшим риском госпитализации, так как при назначении данного вида лечения всем пациентам с нетяжелым течением COVID-19 преимущества будут несущественными (в абсолютном выражении); вместе с тем ряд вариантов лечения следует назначать только лицам, затронутым наивысшим риском госпитализации, в как можно более короткие сроки от начала заболевания. Экспертная группа определила, что риск госпитализации в связи с COVID-19, превышающий 10%, представляет собой пороговое значение, при котором большинство людей с нетяжелым течением заболевания предпочтет назначение терапии (см. раздел 7). Достоверное выявление лиц, затронутых наивысшим риском, представляет трудности ввиду различия характеристик эволюции вируса и охвата вакцинацией в глобальном масштабе, что делает необходимым валидацию моделей в условиях на местах. В ходе текущего систематического обзора 232 предиктивных моделей риска COVID-19 в период до распространения варианта «омикрон» было выявлено два перспективных инструмента прогнозирования риска (18). Оба инструмента содержат указания на то, что к типовым характеристикам лиц, затронутых наивысшим риском, относятся пожилой возраст, иммуносупрессия и/или наличие хронических заболеваний, тогда как дополнительным фактором риска является отсутствие вакцинации. 11 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 12 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.2. Флувоксамин (опубликовано 14 июля 2022 г.) Для пациентов с нетяжелым течением COVID-19 Практические сведения Группой сделана рекомендация не применять флувоксамин для лечения пациентов с COVID-19 вне клинических испытаний, в связи с чем разработка практических соображений по использованию этого препарата малоактуальна. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Применение флувоксамина у пациентов с нетяжелым течением COVID-19, по-видимому, характеризуется незначительным или нулевым эффектом в отношении смертности, а также может характеризоваться слабым или нулевым эффектом в отношении госпитализации, тогда как сведений о времени до разрешения симптомов и нежелательных явлениях, приводящих к отмене препарата, не представлено. Группа по разработке руководящих принципов пришла к выводу о том, что соотношение преимуществ и возможного вреда свидетельствует о нецелесообразности данного вида лечения. При проведении планового сравнительного анализа терапии флувоксамином и стандартного лечения в подгруппах по критериям возраста и времени до появления симптомов не было выявлено различий относительного эффекта, тогда как проведение оценки по критерию тяжести заболевания было невозможным, так как в исследование набирали пациентов только с нетяжелым течением COVID-19. Убедительность фактических данных В основу резюме фактических данных было положено три РКИ, включенных в ОДСМА, с участием 2225 пациентов. Набор в самое масштабное исследование (n=1480) проводился исключительно в Бразилии (19). Степени убедительности фактических данных были следующими: средняя в отношении смертности (ввиду крайне косвенного характера данных), низкая в отношении искусственной вентиляции легких (ввиду крайне косвенного характера данных, неоднозначности трактовки данных, а также оснований предполагать риск систематической ошибки) и госпитализации (ввиду существенной неоднозначности трактовки данных и риска систематической ошибки). Признавая, что на основании других опубликованных метаанализов степень убедительности фактических данных может быть оценена иначе (20), члены группы указали, что результаты самого крупного исследования могут характеризоваться систематической ошибкой, так как в нем имело место преждевременное прекращение терапии на фоне видимого улучшения. Члены группы подчеркнули, что, несмотря на заранее установленные правила прекращения терапии, принятие данного решения основывалось на оценке эффекта в отношении комбинированного конечного результата спорной значимости, тогда как количество важных событий было более низким. Кроме того, группа выразила обеспокоенность в отношении практической значимости исследования, проведенного на территории всего одной страны. Ценностные ориентиры и предпочтения Принимая во внимание согласованное заявление о ценностных ориентирах и предпочтениях (см. раздел 7), группа по разработке руководящих принципов предположила, что, с учетом имеющихся фактических данных, практически все надлежащим образом информированные пациенты предпочтут отказаться от лечения COVID-19 при помощи флувоксамина. Группа по разработке руководящих принципов не согласилась с тем, что иные аспекты, такие как соображения практической осуществимости, приемлемости, равноправия и стоимости, повлияют на данную рекомендацию. В частности, при разработке данных рекомендаций, касающихся средств для лечения COVID-19, группа не приняла во внимание возможную роль флувоксамина как антидепрессанта. Ресурсная оснащенность и другие аспекты Группа признала, что эффективные альтернативы лечения нетяжелой формы COVID-19 характеризуются высокой стоимостью, что может ограничивать их доступность в районах с ограниченными ресурсами. С другой стороны, хотя стоимость флувоксамина относительно невысока по сравнению с другими средствами для лечения COVID-19, и, кроме того, данный препарат широко доступен, в том числе в районах с низким уровнем дохода, фактические данные не свидетельствуют в пользу применения флувоксамина для лечения нетяжелой формы COVID-19. Хотя стоимость флувоксамина низка, группа по разработке руководящих принципов выразила обеспокоенность в связи с риском Только в условиях проведения исследований Новые сведения Авторы не рекомендуют применение флувоксамина за исключением случаев клинических испытаний (рекомендуется применять только в рамках научных исследований). • Для пациентов с нетяжелым течением COVID-19 рекомендуется ряд вариантов лечения, в том числе комбинация нирматрелвира и ритонавира, молнупиравир и ремдесивир. • Для выбора конкретных вариантов лечения следует руководствоваться информацией раздела 6.1, а также инструментом содействия принятию решений, в котором разъяснены польза и вред различных вариантов. 13 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) отвлечения усилий и ресурсов от мероприятий, которые с большей вероятностью могут принести пользу. Во избежание возможного толкования текста рекомендаций как документа, закрепляющего и обосновывающего отсутствие равноправного доступа к более эффективным препаратам, группа сочла необходимым подчеркнуть важность доступа к эффективным средствам лечения на более равноправной основе. Обоснование При вынесении на основании фактических данных рекомендации не применять флувоксамин у пациентов с нетяжелым течением COVID-19 за исключением условий клинических испытаний группа подчеркнула, что точный механизм данного действия не выяснен, и отметила низкую степень убедительности фактических данных, указывающих на слабый или нулевой эффект в отношении госпитализации и искусственной вентиляции легких, среднюю степень убедительности данных о слабом или нулевом эффекте в отношении смертности, а также отсутствие достоверных данных о серьезных нежелательных эффектах, которые могут быть вызваны приемом данного препарата, обладающего значимыми лекарственными взаимодействиями. Группа отметила, что в ходе самого крупного исследования отмена испытуемого препарата чаще наблюдалась в группе лечения флувоксамином по сравнению с группой плацебо. Отмечая, что имеются эффективные альтернативы для лекарственной терапии нетяжелой формы COVID-19, группа по разработке руководящих принципов, тем не менее, предположила, что важных различий в ценностных ориентирах и предпочтениях пациентов выявлено не будет. Кроме того, члены группы усомнились в том, что другие соображения, например факторы, касающиеся ресурсов, практической осуществимости и равноправия (см. резюме данных факторов в разделе «Фактические сведения, лежащие в основе данной рекомендации»), оказывают влияние на эту рекомендацию. Возможность применения Отдельные группы населения. Ни в одном из рассмотренных исследований не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Тем не менее, экспертная группа не имела оснований предполагать, что ответ на лечение COVID-19 флувоксамином у детей будет отличаться. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: флувоксамин Сравнение: без применения флувоксамина Резюме В основу ОДСМА по флувоксамину были положены данные трех РКИ с участием 2225 пациентов с нетяжелым течением заболевания в амбулаторных условиях. Все три РКИ были зарегистрированы; два из них опубликованы в рецензируемых журналах. Все три исследования проводились в амбулаторных условиях. Ни в одном из включенных исследований не участвовали дети. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения флувоксамина по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (1). По данным исследования TOGETHER (19), не было выявлено достоверного эффекта в подгруппах в отношении первичной конечной точки в разбивке по возрасту (дети – взрослые – пожилые люди) и времени от появления симптомов (0–3 дня – 4–7 дней). Проведение планового анализа в подгруппах по критерию тяжести заболевания, возраста и хронических заболеваний (абсолютные эффекты), серологического статуса и прививочного статуса было невозможным ввиду недостаточности имеющихся данных. Исход Период времени Результаты исследования и количественные показатели Сравнение без применения флувоксамина Вмешательство флувоксамин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,68 (95% ДИ: 0,33– 1,32) На основании данных по 1649 пациентам в 2 исследованиях (рандомизированны е контролируемые) 4 на 1000 3 на 1000 Средняя Ввиду крайне косвенного характера данных1 Предположительно, влияние на показатель смертности минимально или отсутствует Разница: сокращение на 1 случай на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 1 случай) 14 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение без применения флувоксамина Вмешательство флувоксамин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Искусственная вентиляция легких Отношение шансов: 0,73 (95% ДИ: 0,38–1,4) На основании данных по 1649 пациентам в 2 исследованиях (рандомизированны е контролируемые) 18 на 1000 13 на 1000 Низкая Ввиду крайне косвенного характера данных и неоднозначности их трактовки2 Вероятно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует Разница: сокращение на 5 случаев на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 7 случаев) Поступление в стационар Высокий риск Отношение шансов: 0,7 (95% ДИ: 0,34–1,23) На основании данных по 2196 пациентам в 3 исследованиях (рандомизированны е контролируемые) 35 на 1000 25 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных3 Вероятно, применение флувоксамина приводит к снижению сроков госпитализации Разница: сокращение на 10 случаев на 1000 (ДИ 95% сокращение на 23 случая – увеличение на 8 случаев) Поступление в стационар Крайне высокий риск Отношение шансов: 0,7 (95% ДИ: 0,34– 1,23) На основании данных по 2196 пациентам в 3 исследованиях (рандомизированны е контролируемые) 60 на 1000 43 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных4 Применение флувоксамина, вероятно, приводит к снижению сроков госпитализации Разница: сокращение на 17 случаев на 1000 (95% ДИ: сокращение на 39 случаев – увеличение на 13 случаев) Поступление в стационар Наивысший риск Отношение шансов: 0,7 (95% ДИ: 0,34– 1,23) На основании данных по 2196 пациентам в 3 исследованиях (рандомизирова нные контролируемые ) 100 на 1000 72 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных 5 Применение флувоксамина, вероятно, приводит к снижению сроков госпитализации Разница: сокращение на 28 случаев на 1000 (95% ДИ: сокращение на 64 случая – увеличение на 20 случаев) Нежелательные явления, приводящие к отмене препарата Нет данных Влияние флувоксамина не определено Время до исчезновения симптомов Нет данных Влияние флувоксамина не определено 15 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение флувоксамина, вероятно, оказывает существенное влияние на показатель смертности. 2. Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. Неоднозначность трактовки данных: существенная. 3. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. 4. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. 5. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: флувоксамин Сравнение: комбинация нирматрелвира и ритонавира Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство флувоксамин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность 0 на 1000 3 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных и высокого риска систематической ошибки1 Влияние на снижение показателя смертности остается крайне неопределенным Разница: увеличение на 3 случая на 1000 (95% ДИ: увеличение на 1 случай – увеличение на 5 случаев) Искусственная вентиляция легких 18 на 1000 13 на 1000 Нет данных2 Влияние на потребность в искусственной вентиляции легких не определено Разница: сокращение на 5 случаев на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 7 случаев) Поступление в стационар Отношение шансов: 4,54 (95% ДИ: 1,32– 12,78) (рандомизированны е контролируемые) 5 на 1000 22 на 1000 Низкая Ввиду существенной неоднозначности трактовки данных и риска систематической ошибки 3 Вероятно, применение комбинации нирматрелвира и ритонавира способствует сокращению госпитализации на более продолжительные сроки, чем применение флувоксамина Разница: увеличение на 17 случаев на 1000 (ДИ 95% увеличение на 2 случая – увеличение на 55 случаев) Нежелательные явления, приводящие к отмене препарата Нет данных Влияние на нежелательные эффекты не определено Время до исчезновения симптомов Нет данных Влияние на время до клинического улучшения состояния пациентов не определено 16 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR были чрезвычайно сжатыми для определения преимуществ. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение флувоксамин может оказать существенное влияние на показатель смертности. Неоднозначность трактовки данных: существенная. Количество событий было крайне малым. 2. Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. Неоднозначность трактовки данных: существенная. 3. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира (EPIC-HR) были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: флувоксамин Сравнение: молнупиравир Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство флувоксамин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 5,74 (95% ДИ: 0,95–56,11) (рандомизированные контролируемые) 0,4 на 1000 2 на 1000 Низкая Ввиду крайне косвенного характера данных и неоднозначности их трактовки11 Вероятно, влияние на смертность минимально или отсутствует Разница: увеличение на 1,6 случая на 1000 (95% ДИ: сокращение на 0,02 случая – увеличение на 21,56 случая) Искусственная вентиляция легких Отношение шансов: 1,77 (95% ДИ: 0,19–10,6) (рандомизированные контролируемые) 8 на 1000 14 на 1000 Очень низкая ввиду крайне косвенного характера данных и крайней неоднозначности трактовки2 Влияние на потребность в искусственной вентиляции легких не определено Разница: увеличение на 6 случаев на 1000 (ДИ 95%: сокращение на 6 случаев – увеличение на 71 случай) Поступление в стационар Отношение шансов: 1,31 (95% ДИ: 0,52–2,98) (рандомизированные контролируемые) 19 на 1000 25 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных3 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 6 случаев на 1000 (ДИ 95%: сокращение на 9 случаев – увеличение на 36 случаев) Нежелательные явления, приводящие к отмене препарата Нет данных Влияние на нежелательные эффекты не определено Время до исчезновения симптомов Нет данных Влияние на время до исчезновения симптомов не определено 1. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение флувоксамина может оказать существенное влияние на показатель смертности. Неоднозначность трактовки данных: существенная. Количество событий было крайне малым. 2. Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. Неоднозначность трактовки данных: крайняя. 3. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. 17 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: флувоксамин Сравнение: ремдесивир Исход Период времени Результаты исследования и количественные показатели Сравнение ремдесивир Вмешательство флувоксамин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,87 (95% ДИ: 0,27–2,85) (рандомизированные контролируемые) 3 на 1000 3 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных1 Вероятно, влияние на смертность минимально или отсутствует Разница: сокращение на 0 случаев на 1000 (ДИ 95% сокращение на 2 случая – увеличение на 6 случаев) Искусственная вентиляция легких Отношение шансов: 1,63 (95% ДИ: 0,19–11,23) (рандомизированные контролируемые) 8 на 1000 13 на 1000 Очень низкая Ввиду крайне косвенного характера данных и крайней неоднозначности трактовки2 Влияние на потребность в искусственной вентиляции легких не определено Разница: увеличение на 5 случаев на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 75 случаев) Поступление в стационар Отношение шансов: 2,76 (95% ДИ: 0,62–12,07) (рандомизированные контролируемые) 9 на 1000 24 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных3 Вероятно, применение ремдесивира способствует сокращению госпитализации на более продолжительные сроки, чем применение флувоксамина Разница: увеличение на 15 случаев на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 90 случаев) Нежелательные явления, приводящие к отмене препарата Нет данных Влияние на нежелательные эффекты не определено Время до исчезновения симптомов Нет данных Влияние на время до исчезновения симптомов не определено • Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение флувоксамин может оказать существенное влияние на показатель смертности. Неоднозначность трактовки данных: существенная. Количество событий было крайне малым. • Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. Неоднозначность трактовки данных: крайняя. • Неоднозначность трактовки данных: крайняя. 6.2.1. Механизм действия Флувоксамин является селективным ингибитором обратного захвата серотонина (СИОЗС), который одобрен к применению как антидепрессант. Противодепрессивный эффект флувоксамина связан с ингибированием серотонинового транспортера в головном мозге, что способствует повышению концентрации серотонина в синаптической щели. Предложен ряд гипотетических механизмов противовоспалительного и противовирусного действия препарата при COVID-19 (21)(22). Прежде всего, предполагают, что противовоспалительное действие обусловлено ингибированием транспортера серотонина в тромбоцитах и/или легких, однако это предположение основано на косвенных данных модели заболевания, отличного от COVID-19. Во-вторых, непрямое противовирусное действие объясняют агонизмом с сигма-1 рецептором, который, по некоторым данным о других вирусах, принимает участие в процессе репликации РНК, вместе с тем, не имеется опубликованных в настоящее время доклинических исследований, которые бы непосредственно подтверждали или опровергали данный механизм при COVID-19. Таким образом, для установления достоверности фактов необходима интерпретация косвенных данных о противовоспалительном или противовирусном действии, которые в настоящее время не доказаны в доклинических исследованиях и не связаны непосредственно с механизмом действия и точкой приложения при депрессии. 18 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.3. Колхицин (опубликовано 14 июля 2022 г.) Для пациентов с нетяжелым течением COVID-19 Практические сведения Группа по разработке руководящих принципов вынесла настоятельную рекомендацию не использовать колхицин для лечения пациентов с нетяжелой формой COVID-19, в связи с чем разработка практических соображений по использованию этого препарата малоактуальна. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред При использовании у пациентов с нетяжелым течением COVID-19 колхицин, по-видимому, оказывает слабое влияние либо не оказывает влияния на смертность, а также потребность в искусственной вентиляции легких, может оказывать слабое или нулевое влияние на потребность в госпитализации, а также может повышать вероятность нежелательных явлений, приводящих к отмене препарата. Группа обсудила риски лекарственных взаимодействий, а также проблему узкого терапевтического окна колхицина, особенно при назначении пациентам с печеночной или почечной недостаточностью либо с риском данных патологий. Колхицин может обладать выраженной токсичностью, в отдельных случаях приводящей к летальным исходам. При проведении планового сравнительного анализа терапии колхицином и стандартного лечения в подгруппах не было выявлено различий относительного эффекта по критерию тяжести заболевания и возраста (дети, взрослые, пожилые), тогда как сведения в отношении появления симптомов отсутствуют. Убедительность фактических данных В основу резюме фактических данных по колхицину был положен систематический обзор с охватом 13 исследований, в которых приняли участие 18 172 человека. Наибольший объем фактических сведений был получен в отношении смертности, тогда как по другим конечным результатам информация была неполной (например, 598 участников с проявлениями нежелательных эффектов лекарственных средств в пяти исследованиях). Исследование с участием 4488 человек (23), ставшее практически единственным источником фактических данных по госпитализации, было прекращено досрочно. Степень убедительности фактических данных была оценена следующим образом: средняя в отношении смертности и искусственной вентиляции легких (оценка снижена в связи с косвенным характером данных); низкая в отношении поступления в стационар (оценка снижена в связи с косвенным характером данных и риском систематической ошибки); низкая в отношении нежелательных явлений, приводящих к отмене препарата (оценка снижена в связи с неоднозначностью трактовки и риском систематической ошибки). Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что с учетом имеющихся фактических данных по соотношению пользы и вреда практически все надлежащим образом информированные пациенты будут склонны отказаться от применения колхицина. Группа по разработке руководящих принципов не согласилась с тем, что другие аспекты, такие как соображения практической осуществимости, приемлемости, равноправия и стоимости, повлияют на данную рекомендацию. Ресурсная оснащенность и другие аспекты Группа признала, что эффективные альтернативы лечения нетяжелой формы COVID-19 характеризуются высокой стоимостью, что может ограничивать их доступность в районах с ограниченными ресурсами. С другой стороны, хотя стоимость колхицина относительно невысока по сравнению с другими средствами для лечения COVID-19, и, кроме того, данный препарат широко доступен, в том числе в районах с низким уровнем дохода, фактические данные не свидетельствуют в пользу применения колхицина для лечения нетяжелой формы COVID-19. Хотя стоимость колхицина низка, группа по разработке руководящих принципов выразила обеспокоенность в связи с риском отвлечения усилий и ресурсов от мероприятий, которые с большей вероятностью могут принести пользу. Во избежание вероятного толкования текста рекомендаций как документа, закрепляющего и обосновывающего отсутствие равноправного доступа к более эффективным препаратам, группа сочла необходимым подчеркнуть важность доступа к эффективным средствам лечения на более равноправной основе. Настоятельная рекомендация не применять Новые сведения Не рекомендуется лечение с использованием колхицина (настоятельная рекомендация не применять). • Для пациентов с нетяжелым течением COVID-19 рекомендуется ряд вариантов лечения, в том числе комбинация нирматрелвира и ритонавира, молнупиравир и ремдесивир. • Для выбора конкретных вариантов лечения следует руководствоваться информацией раздела 6.1, а также инструментом содействия принятию решений, в котором разъяснены польза и вред различных вариантов. 19 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Обоснование При вынесении на основании фактических данных настоятельной рекомендации не использовать колхицин у пациентов с нетяжелым течением COVID-19, группа по разработке руководящих принципов подчеркнула наличие данных средней степени убедительности об отсутствии влияния на смертность и потребность в искусственной вентиляции легких, а также данных низкой степени убедительности об отсутствии влияния на госпитализацию и вместе с тем возможный вред в связи с проводимым лечением. В частности, группа подчеркнула, что наличие риска диареи, цитопении и других видов токсичности, особенно у пациентов с почечной недостаточностью или риском данной патологии, вероятно играет важную роль для пациентов с нетяжелым течением COVID-19. Отмечая, что имеются эффективные альтернативы для лекарственной терапии нетяжелой формы COVID-19, группа по разработке руководящих принципов, тем не менее, предположила, что важных различий в ценностных ориентирах и предпочтениях пациентов выявлено не будет. Кроме того, члены группы усомнились в том, что другие соображения, например факторы, касающиеся ресурсов, практической осуществимости и равноправия (см. резюме данных факторов в разделе «Фактические сведения, лежащие в основе данной рекомендации»), оказывают влияние на эту рекомендацию. Возможность применения Отдельные группы населения. Ни в одном из рассмотренных исследований не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Тем не менее, экспертная группа не имела оснований предполагать, что ответ на лечение COVID-19 колхицином у детей будет отличаться. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: колхицин Сравнение: стандарт оказания помощи Резюме В систематический обзор оп колхицину вошли 13 исследований с участием 18 172 пациентов. Все исследования, за исключением трех, были зарегистрированы. Ни в одном из исследований не участвовали дети. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения колхицина по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (1). По данным исследования COLCORONA (23), не было выявлено достоверного эффекта в подгруппах в отношении первичной конечной точки в разбивке по возрасту (дети – взрослые – пожилые люди) и тяжести заболевания (нетяжелая форма – тяжелая форма). Проведение планового анализа в подгруппах по критерию времени до появления симптомов, возраста и хронических заболеваний (абсолютные эффекты), серологического статуса и прививочного статуса было невозможным ввиду недостаточности имеющихся данных. Исход Период времени Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Колхицин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,84 (95% ДИ: 0,5–1,17) Данные по 17 914 пациентам, полученные в 10 исследованиях. (рандомизированные контролируемые) 4 на 1000 3 на 1000 Средняя Ввиду крайне косвенного характера данных1 Предположительно, колхицин оказывает слабое влияние либо не оказывает влияние на показатель смертности Разница: сокращение на 1 случай на 1000 (95% ДИ: сокращение на 2 случая – увеличение на 1 случай) Искусственная вентиляция легких Отношение шансов: 0,75 (95% ДИ: 0,37–1,26) На основании данных по 12 746 пациентам в 5 исследованиях (рандомизированные контролируемые) 9 на 1000 7 на 1000 Средняя Ввиду крайне косвенного характера данных2 Предположительно, колхицин оказывает слабое влияние либо не оказывает влияние на потребность в искусственной вентиляции легких Разница: сокращение на 2 случая на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 2 случая) 20 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Колхицин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Поступление в стационар Риск в исследованиях Отношение шансов: 0,68 (95% ДИ: 0,27–1,57) На основании данных по 4949 пациентам в 3 исследованиях (рандомизированные контролируемые) 35 на 1000 24 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Предположительно, колхицин оказывает слабое влияние либо не оказывает влияние на поступление в стационар Разница: сокращение на 1 случай на 1000 (95% ДИ: сокращение на 25 случаев – увеличение на 19 случаев) Поступление в стационар Крайне высокий риск Отношение шансов: 0,68 (95% ДИ: 0,27–1,57) На основании данных по 4949 пациентам в 3 исследованиях. (рандомизированные контролируемые) 60 на 1000 42 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных4 Предположительно, колхицин оказывает слабое влияние либо не оказывает влияние на поступление в стационар Разница: сокращение на 18 случаев на 1000 (95% ДИ: сокращение на 43 случая – увеличение на 31 случай) Поступление в стационар Наивысший риск Отношение шансов: 0,68 (95% ДИ: 0,27–1,57) На основании данных по 4949 пациентам в 3 исследованиях. (рандомизированные контролируемые) 100 на 1000 70 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных5 Вероятно, колхицин оказывает слабое влияние либо не оказывает влияние на поступление в стационар Разница: сокращение на 30 случаев на 1000 (95% ДИ: сокращение на 71 случай – увеличение на 49 случаев) Нежелательные явления, приводящие к отмене препарата На основании данных по 598 пациентам в 5 исследованиях. (рандомизированные контролируемые) 0 на 1000 34 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных6 Вероятно, применение колхицина повышает риск развития серьезных побочных явлений, приводящих к отмене препарата Разница: увеличение на 34 случая на 1000 1. Косвенный характер данных: существенный. 2. Косвенный характер данных: существенный. Неоднозначность трактовки данных: несущественная. Доверительный интервал накрывает область, соответствующую полезному эффекту, выраженному в средней степени. 3. Неоднозначность трактовки данных: существенная. Верхняя граница доверительного интервала накрывает область слабого и несущественного влияния на госпитализацию (снижение на 4 случая на 1000). 4. Неоднозначность трактовки данных: существенная. Верхняя граница доверительного интервала накрывает область слабого и несущественного влияния на госпитализацию (снижение на 4 случая на 1000). 5. Неоднозначность трактовки данных: крайняя. 6. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: существенная. 21 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.3.1. Механизм действия Колхицин является противовоспалительным препаратом, применяемым для лечения подагры, рецидивирующего перикардита, семейной средиземноморской лихорадки и купирования других воспалительных процессов. Предложен ряд механизмов действия, которые теоретически могут объяснять подавление провоспалительного процесса при COVID-19 (24)(25): к ним относится снижения хемотаксиса нейтрофилов, ингибирование сигналинга с участием инфламмасом, а также снижение выработки цитокинов, таких как интерлейкин-1b (IL-1b). На момент публикации этих временных рекомендаций не имелось обнародованных сведений, полученных в модели инфекции SARS-CoV-2 у животных, в пользу или в опровержение факта эффективности либо вреда применения колхицина на доклиническом этапе при соответствующем патологическом процессе. Предполагают, что в данном случае механизм действия сходен с уже известным механизмом, благодаря которому колхицин одобрен для применения при ряде заболеваний, однако для убедительного обоснования данного эффекта при COVID-19 необходимо согласиться с наличием у COVID-19 и других заболеваний сходных характеристик. Изученные дозировки и схемы терапии при COVID-19 существенно различаются в разных исследованиях. Диапазон дозировок в исследованиях, включенных в СМА, составлял от 0,5 до 2 мг в день, продолжительность курсов составляла от 6 до 30 дней, в некоторых исследованиях препарат назначали один раз в сутки, тогда как в других исследованиях кратность приема составляла два или три раза в сутки. Кроме того, в ряде исследований применялись изменяемые на протяжении лечения режимы, при которых терапию начинали с определенной дозировки или кратности приема с последующим переходом к другой дозировке или кратности по истечении определенного времени. Фармакокинетика колхицина характеризуется линейной зависимостью от введенной дозы в диапазоне от 0,5 мг до 1,5 мг (26)(27), вместе с тем значительный разброс сведений исследований, включенных в СМА, не позволяет однозначно трактовать различия исходов, связанных с различными дозировками и кратностью приема. 22 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.4. Комбинация нирматрелвира и ритонавира (опубликовано 22 апреля 2022 г.) Справочная информация Рекомендации по применению комбинации нирматрелвира и ритонавира для лечения пациентов с нетяжелым течением COVID-19 были опубликованы 22 апреля 2022 г. в десятой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Рекомендации были выпущены в рамках ОДСМА, посвященного лекарственной терапии, после опубликования результатов двух РКИ (1). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся комбинации нирматрелвира и ритонавира, внесено не было. Для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации Практические сведения Пути введения, дозировка и продолжительность применения. Дополнительные соображения изложены в трех резюме практических вопросов (комбинация нирматрелвира и ритонавира при COVID-19, прием комбинации нирматрелвира и ритонавира при COVID-19, безопасность и мониторинг пациентов, получающих комбинацию нирматрелвира и ритонавира для лечения COVID-19 – только на английском языке). Ниже кратко обобщены основные положения. • По данным масштабных исследований, которые были положены в основу этой рекомендации и в которых изучалась схема лечения, рекомендуется применение комбинации нирматрелвира и ритонавира в следующей дозировке: 300 мг (две таблетки по 150 мг) нирматрелвира и 100 мг ритонавира каждые 12 часов ежедневно в течение 5 дней. • При почечной недостаточности (СКФ 30–59 мл/мин) сниженная дозировка должна составлять: 150 мг нирматрелвира и 100 мг ритонавира каждые 12 часов ежедневно в течение 5 дней. • Применение препарата на фоне заболевания необходимо начинать как можно раньше. В исследованиях, которые были рассмотрены, применение комбинации нирматрелвира и ритонавира начинали в течение 5 дней от дебюта заболевания. • Вместе с тем группа пришла к выводу о том, что комбинацию нирматрелвира и ритонавира не следует назначать детям, кормящим или беременным женщинам с COVID-19. Клиницист должен тщательно оценить возможные лекарственные взаимодействия у любого пациента, которому планируется назначение комбинации нирматрелвира и ритонавира. Для этого может быть использован инструмент проверки лекарственных взаимодействий, разработанный университетом Ливерпуля (28). Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Для пациентов группы наивысшего риска, у которых на фоне применения комбинации нирматрелвира и ритонавира возможно существенное снижение вероятности госпитализации, преимущества очевидно превосходят вред, в связи с чем может быть сделана настоятельная рекомендация в пользу применения препарата. Настоятельная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием комбинации нирматрелвира и ритонавира (настоятельная рекомендация в пользу применения). • Информация для содействия выявлению пациентов, затронутых наивысшим риском, содержится в разделе 6.1. • Доступен ряд вариантов лечения: см. инструмент содействия принятию решений, в котором представлены сведения о пользе и вреде применения комбинации нирматрелвира и ритонавира, молнупиравира, ремдесивира и моноклональных антител. • Группа по разработке руководящих принципов пришла к выводу о том, что комбинация нирматрелвира и ритонавира является наилучшим вариантом лечения, так как данные средства, вероятно, обладают большей эффективностью в отношении профилактики госпитализации по сравнению с альтернативами, обладают меньшим количеством эффектов, вызывающих обеспокоенность, по сравнению с молнупиравиром и более удобны при приеме по сравнению с ремдесивиром или антителами, требующими внутривенного введения. • Настоятельная рекомендация в пользу применения не относится к беременным женщинам, детям или лицам, у которых могут иметь место опасные лекарственные взаимодействия (большая группа препаратов взаимодействует с комбинацией нирматрелвира и ритонавира, см. раздел «Механизм действия»). • Применение комбинации нирматрелвира и ритонавира должно начинаться как можно раньше от момента появления симптомов, в идеальном случае в течение 5 дней. 23 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) У пациентов с нетяжелым течением COVID-19 применение комбинации нирматрелвира и ритонавира, возможно, приводит к снижению частоты госпитализации (средняя степень убедительности данных). Влияние препарата на смертность, вероятно, невелико или отсутствует (низкая степень убедительности данных). Данных о времени до исчезновения симптомов или искусственной вентиляции легких не имеется. Назначение терапии не влечет за собой повышения вероятности нежелательных явлений, приводящих к отмене препарата (высокая степень убедительности данных), хотя диарея и дисгвезия (утрата вкусовых ощущений) в группе лечения комбинацией нирматрелвира и ритонавира наблюдались чаще, чем в группе плацебо. Группа по разработке руководящих принципов признала недостаток сведений, относящихся к развитию резистентности, и для обоснования рекомендаций необходим существенно больший объем данных. Убедительность фактических данных В основу резюме фактических данных по комбинации нирматрелвира и ритонавира было положено два включенных в ОДСМА исследования (EPIC-SR и EPIC-HR) с участием 3100 пациентов (1)(29)(30). Степень убедительности фактических данных была оценена следующим образом: средняя в отношении сокращения сроков госпитализации (оценка снижена ввиду неоднозначности трактовки данных и риска систематической ошибки); низкая в отношении смертности (оценка снижена ввиду существенной неоднозначности трактовки данных и их косвенного характера); высокая в отношении нежелательных явлений, приводящих к отмене препарата. Оценка убедительности фактических данных, касающихся диареи и дисгвезии, не проводилась. Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных ввиду их косвенного характера, обусловленного главным образом ограниченной доступностью разработанного эмпирическим путем метода прогнозирования риска, позволяющего определять риск госпитализации у отдельных пациентов (31). Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что почти все надлежащим образом информированные пациенты с крайне высоким риском госпитализации предпочтут получить лечение комбинацией казиривимаба и имдевимаба. Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость По-видимому, лечение комбинацией нирматрелвира и ритонавира не будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Данный факт подчеркивает необходимость создания запасов комбинированного препарата нирматрелвира и ритонавира для лиц, находящихся в группе крайне высокого риска. Стоимость и доступность препарата в странах с низким и средним уровнем дохода (СНСД) может представлять существенные препятствия. Доступ к услугам, в том числе диагностическому тестированию и лечению, в первые пять дней от момента появления симптомов нередко бывает затруднен для лиц, находящихся в неблагоприятном социально-экономическом положении, что, в свою очередь, ограничивает доступность вмешательств. Таким образом, выполнение вмешательства у пациентов с крайне высоким риском может обострять неравенство в области здравоохранения. В масштабе стран важно интегрировать схему маршрутизации лиц с COVID-19 в механизм обслуживания пациентов с нетяжелым течением COVID-19 (то есть в систему первичной медико-санитарной помощи или общинные учреждения). Данные рекомендации должны обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этому средству лечения. Одним из примеров служит опубликованное 17 декабря 2021 г. Седьмое приглашение ВОЗ для производителей лекарственных средств для лечения COVID-19 к подаче предварительных заявок на участие в оценке продукции в Департамент преквалификации ВОЗ. В случае, если по итогам такой оценки будет установлено соответствие средства и производителя (а также клинической базы) требованиям стандартов, рекомендованных ВОЗ, средство будет включено в перечень медицинской продукции, одобренной для закупок организациями системы ООН и другими участниками. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Доступ к диагностическим средствам для выявления вируса SARS-CoV-2. Так как в данной рекомендации подчеркнута необходимость проведения лечения комбинацией нирматрелвира и ритонавира в идеальном случае в течение 5 дней с момента появления симптомов, важнейшее значение для практической работы имеет расширение доступа и обеспечение надлежащего использования диагностических тестов. В этой связи для улучшения доступа к лекарственным средствам, особенно тем, которые применимы в ранний период заболевания, необходимо наличие и использование надежных и своевременных диагностических тестов на инфекцию, вызванную вирусом SARS-CoV-2. Совершенствование ранней диагностики в общинных учреждениях и учреждениях первичного звена здравоохранения может быть достигнуто благодаря надлежащему использованию диагностических экспресс-тестов, например, тестов на определение антигенов. Вместе с тем системы здравоохранения должны накопить опыт выбора и практического использования экспресс-тестов, которые наиболее применимы к условиям на местах. Обоснование Настоятельная рекомендация в пользу применения препарата у лиц, затронутых крайне высоким риском госпитализации, основана на фактических данных средней степени убедительности о значительном снижении относительного риска госпитализации и данных высокой степени убедительности об отсутствии нежелательных эффектов, приводящих в отмене препарата. По-видимому, у данных лиц может быть достигнуто важное снижение абсолютного риска госпитализации по 24 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) сравнению с пациентами, которые не получают комбинацию нирматрелвира и ритонавира. Альтернативы, а также комбинированные средства лечения Ранее группой по разработке руководящих принципов была сделана условная рекомендация в пользу применения молнупиравира (см. раздел 6.6) у пациентов с нетяжелым течением инфекции, затронутых наивысшим риском, тогда как в этом обновленном издании документа – условная рекомендация в отношении ремдесивира (см. раздел 6.5). При косвенном сравнении в группах крайне высокого и наивысшего риска было установлено, что прием комбинации нирматрелвира и ритонавира может способствовать большему сокращению продолжительности госпитализации, чем прием молнупиравира (низкая степень убедительности); вместе с тем такие различия были минимальными или нулевыми при сравнении с приемом ремдесивира (низкая степень убедительности). В отсутствие данных о прямом сравнении, а также в связи с низкой степенью убедительности косвенных сравнений группа по разработке руководящих принципов предпочла не выносить сравнительные рекомендации в отношении различных препаратов; вместо этого сделано указание на то, что комбинация нирматрелвира и ритонавира может быть более предпочтительной в связи с большей эффективностью, чем стандарт оказания помощи (средняя степень убедительности), а окончательный выбор должен определяться практическими соображениями, такими как простота введения и профили риска. Фактических данных в пользу комбинированного использования других противовирусных препаратов не имеется, в связи с чем данный подход группой не рекомендован. Возможность применения Так как во всех рассмотренных РКИ участвовали взрослые пациенты за исключением беременных, применимость данной рекомендации к детям, кормящим и беременным женщинам остается невыясненной. Вместе с тем группа пришла к выводу о том, что комбинацию нирматрелвира и ритонавира не следует назначать детям, кормящим или беременным женщинам с COVID-19. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: комбинация нирматрелвира и ритонавира Сравнение: комбинация нирматрелвира и ритонавира Резюме В основу ОДСМА по комбинации нирматрелвира и ритонавира были положены данные двух РКИ (EPIC-SR и HR) с участием 3100 пациентов с нетяжелым течением заболевания в амбулаторных условиях. Оба РКИ были зарегистрированы; одно было опубликовано в рецензируемом журнале (30). Ни в одном из включенных исследований не участвовали дети или беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения комбинации нирматрелвира и ритонавира по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (3). Возможность выполнения планового анализа в подгруппах была ограничена доступностью данных, хотя наряду с этим в подгруппах не было выявлено достоверных эффектов, связанных с серологическим статусом и возрастом (набор детей не проводился). Так как все пациенты были невакцинированными, а рандомизация проведена в течение 5 дней от момента появления симптомов, и дополнительных лечебных мероприятий не осуществлялось, проведение указанных видов анализа в подгруппах было невозможным. Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие комбинации нирматрелвира и ритонавира Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней Отношение шансов: 0,04 (95% ДИ: 0–0,67) На основании данных по 3100 пациентам в 2 исследованиях(ран домизированные контролируемые) 6 на 1000 0 на 1000 Низкая ввиду существенной неоднозначности трактовки и косвенного характера данных1 Комбинация нирматрелвира и ритонавира может оказывать слабое воздействие на показатель смертности Разница: сокращение на 6 случаев на 1000 (95% ДИ сокращение на 6 случаев – сокращение на 2 случая) Искусственная вентиляция легких Нет данных Влияние комбинации нирматрелвира и ритонавира не определено 25 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие комбинации нирматрелвира и ритонавира Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Госпитализация Риск в исследованиях Отношение шансов: 0,15 (95% ДИ: 0,06–0,38) На основании данных по 3078 пациентам в 2 исследованиях. (рандомизированные контролируемые) 35 на 1000 5 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных2 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 30 случаев на 1000 (95% ДИ: сокращение на 33 случая – сокращение на 21 случай) Госпитализация Крайне высокий риск Отношение шансов: 0,15 (95% ДИ: 0,06–0,38) На основании данных по 3078 пациентам в 2 исследованиях. (рандомизированные контролируемые) 60 на 1000 9 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных3 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 51 случай на 1000 (95% ДИ: сокращение на 56 случаев – сокращение на 36 случаев) Госпитализация Группа наивысшего риска Отношение шансов: 0,15 (95% ДИ: 0,06–0,38) На основании данных по 3078 пациентам в 2 исследованиях. (рандомизированные контролируемые) 100 на 1000 16 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных4 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 84 случая на 1000 (95% ДИ: сокращение на 93 случая – сокращение на 59 случаев) Нежелательные явления, приводящие к отмене препарата Отношение шансов: 0,48 (95% ДИ: 0,29–0,8) На основании данных по 2246 пациентам в 1 исследовании. (рандомизированные контролируемые) 0 на 1000 0 на 1000 Высокая На фоне приема комбинации нирматрелвира и ритонавира наблюдается минимальный или нулевой риск развития нежелательных явлений, приводящих к отмене препарата Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Время до исчезновения симптомов Нет данных Влияние комбинации нирматрелвира и ритонавира не определено. 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. Применение комбинации нирматрелвира и ритонавира предположительно приводит к снижению смертности у данных пациентов. Неоднозначность трактовки данных: существенная. Общее количество событий составило всего 12 (все в группе плацебо); данные всего одного исследования. 2. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 3. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 4. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 26 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: комбинация нирматрелвира и ритонавира Сравнение: молнупиравир Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней Отношение шансов 0 (95%ДИ: 0–0,29) (рандомизированные контролируемые) 0 на 1000 0 на 1000 Средняя Ввиду крайне косвенного характера данных1 Предположительно, влияние на показатель смертности минимально или отсутствует. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Искусственная вентиляция легких Нет данных Влияние комбинации нирматрелвира и ритонавира не определено. Госпитализация Риск в исследованиях Отношение шансов 0,29 (95% ДИ: 0,1–0,88) (рандомизированные контролируемые) 19 на 1000 6 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных2 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 13 случаев на 1000 (95% ДИ: сокращение на 17 случаев – сокращение на 2 случая) Госпитализация Группа наивысшего риска Отношение шансов 0,29 (95% ДИ: 0,1–0,88) (рандомизированные контролируемые) 57 на 1000 17 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных3 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 40 случаев на 1000 (95% ДИ: сокращение на 51 случай – сокращение на 6 случаев) Госпитализация Группа крайне высокого риска Отношение шансов 0,29 (95% ДИ: 0,1–0,88) (рандомизированные контролируемые) 33 на 1000 17 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных4 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 40 случаев на 1000 (95% ДИ: сокращение на 51 случай – сокращение на 6 случаев) 27 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Нежелательные явления, приводящие к отмене препарата 0 на 1000 0 на 1000 Высокая Различия по критерию риска нежелательных явлений, приводящих к отмене препарата, минимальны или не выявлены. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Время до исчезновения симптомов Нет данных Влияние нирматрелвира/ ритонавира не определено 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. 2. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 3. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 4. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: ремдесивир Сравнение: комбинация нирматрелвира и ритонавира Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней 0 на 1000 3 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки, косвенным характером данных и неоднозначностью их трактовки1 Влияние на смертность не определено Разница: увеличение на 3 случая на 1000 увеличение на 2 случая – увеличение на 5 случаев Искусственная вентиляция легких Нет данных Влияние на потребность в искусственной вентиляции легких остается неопределенным Госпитализация Риск в исследованиях Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 6 на 1000 9 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки данных2 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 3 случая на 1000 (95% ДИ: сокращение на 4 случая – увеличение на 38 случаев) 28 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Госпитализация Крайне высокий риск Отношение шансов 1,64 (95%ДИ: 0,33–7,57) (рандомизированные контролируемые) 9 на 1000 15 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки данных3 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 55 случаев) Поступление в стационар Наивысший риск Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 16 на 1000 26 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки данных4 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 10 случаев на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 94 случая) Нежелательные явления, приводящие к отмене препарата 0 на 1000 9 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных, высокой вероятности систематической ошибки, крайне косвенного характера данных и крайне высокого риска систематической ошибки5 Влияние на развитие нежелательных явлений, приводящих к отмене препарата, не определено Время до исчезновения симптомов Нет данных Влияние комбинации нирматрелвира и ритонавира не определено. 1. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. Неоднозначность трактовки данных: существенная. Небольшое количество событий: всего 50 событий в сравнении ремдесивир – контроль и 11 событий в сравнении молнупиравир – контроль. 2. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 3. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 4. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 5. Риск систематической ошибки: крайне высокий. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. 29 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Для пациентов с нетяжелым течением COVID-19, затронутых низким риском госпитализации Практические сведения Пути введения, дозировка и продолжительность применения. Дополнительные соображения содержатся в практическом резюме. Клиницист должен тщательно оценить возможные лекарственные взаимодействия у любого пациента, которому планируется назначение комбинации нирматрелвира и ритонавира. Для этого может быть использован инструмент проверки лекарственных взаимодействий, разработанный университетом Ливерпуля (28). Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред У пациентов с нетяжелой формой COVID-19 применение комбинации нирматрелвира и ритонавира предположительно приводит к снижению сроков госпитализации. Вместе с тем абсолютная польза для пациентов группы низкого риска крайне мала и, по-видимому, не будет представлять важность для большинства пациентов. Предположительно, комбинация нирматрелвира и ритонавира оказывает слабое влияние либо не оказывает влияние на показатель смертности. Крайне значимыми для пациентов из группы низкого риска госпитализации является отсутствие опубликованных данных о времени до исчезновения симптомов. Вместе с тем в исследовании EPIC-SR сообщается о весьма схожем конечном результате: время до момента сохранения симптомов в пределах легких на протяжении 4 дней подряд либо полного исчезновения симптомов. При проведении анализа по данному критерию медианная продолжительность времени составила 13,0 (95% ДИ: от 12 до 15) дней в группе лечения комбинацией нирматрелвира и ритонавира и 13,0 (95% ДИ: от 11 до 14) дней в группе плацебо (р=0,47). Назначение терапии не влечет за собой повышения вероятности нежелательных явлений, приводящих к отмене препарата, хотя диарея и дисгвезия в группе лечения комбинацией нирматрелвира и ритонавира наблюдались чаще, чем в группе плацебо. Убедительность фактических данных В основу резюме фактических данных по комбинации нирматрелвира и ритонавира было положено два включенных в ОДСМА исследования (EPIC-SR и EPIC-HR) с участием 3100 пациентов (1)(29)(30). Степень убедительности фактических данных была оценена следующим образом: средняя в отношении сокращения сроков госпитализации (оценка снижена ввиду существенной неоднозначности трактовки данных и риска систематической ошибки); низкая в отношении смертности (оценка снижена ввиду существенной неоднозначности трактовки данных и их косвенного характера); высокая в отношении нежелательных явлений, приводящих к отмене препарата. Оценка убедительности фактических данных, касающихся диареи и дисгвезии, не проводилась. Ценностные ориентиры и предпочтения Группа полагает, что большинство пациентов группы низкого риска предпочтет воздержаться от применения препаратов, влияние которых на важные для пациента исходы, по имеющимся фактическим данным, не установлено. Данное соображение особенно касается такого показателя как сокращение периода проявления симптомов, в отношении которого не имеется непосредственных данных в пользу комбинации нирматрелвира и ритонавира. Ресурсная оснащенность и другие аспекты По-видимому, лечение комбинацией нирматрелвира и ритонавира не будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Данный факт подчеркивает необходимость создания запасов комбинированного препарата нирматрелвира и ритонавира для лиц, находящихся в группе наивысшего риска. Обоснование Большинство пациентов, заразившихся COVID-19, затронуты крайне низким риском госпитализации (менее 1%) и крайне низким риском летального исхода. Преимущества комбинации нирматрелвира и ритонавира будут для них минимальными. Группа предположила, что для большинства таких пациентов применение препаратов не будет представлять интереса в Условная рекомендация не применять Новые сведения Рекомендуется не применять комбинацию нирматрелвира и ритонавира (условная рекомендация не применять). • Согласно оценке группы по разработке руководящих принципов, применение комбинации нирматрелвира и ритонавира будет рассматриваться крайне малым количеством пациентов, затронутых низким риском. • В исследованиях противовирусных препаратов участвовали пациенты с определенными факторами риска госпитализации, в связи с чем исходный риск составлял 3%, и данная величина была применена группой при подготовке рекомендации. По-видимому, риск госпитализации в общей популяции будет ниже. • Клиницистам не следует рассматривать применение комбинации нирматрелвира и ритонавира у беременных женщин, детей, а также лиц, у которых могут иметь место опасные лекарственные взаимодействия (примечание: многие препараты вступают во взаимодействие с комбинацией нирматрелвира и ритонавира). 30 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) силу малой пользы. Таким образом, применение комбинации нирматрелвира и ритонавира будет расценено большинством пациентов как целесообразное лишь на фоне определенного порогового уровня риска, что, в свою очередь, означает наличие одного или нескольких факторов риска. Это в особенности касается районов с низким уровнем дохода, в которых перспективность применения комбинации нирматрелвира и ритонавира менее очевидна в свете ресурсных ограничений и аспектов практической осуществимости. Вместе с тем группа по разработке руководящих принципов признает, что значительное количество пациентов может отдавать предпочтение даже незначительному сокращению риска госпитализации, и, следовательно, данная группа лиц будет склонна согласиться с использованием комбинации нирматрелвира и ритонавира; таким образом, вместо настоятельной сделана условная рекомендация. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: комбинация нирматрелвира и ритонавира Сравнение: комбинация нирматрелвира и ритонавира Резюме В основу ОДСМА по комбинации нирматрелвира и ритонавира были положены данные двух РКИ (EPIC-SR и HR) с участием 3100 пациентов с нетяжелым течением заболевания в амбулаторных условиях. Оба РКИ были зарегистрированы; одно было опубликовано в рецензируемом журнале (30). Ни в одном из включенных исследований не участвовали дети или беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения комбинации нирматрелвира и ритонавира по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (3). Возможность выполнения планового анализа в подгруппах была ограничена доступностью данных, хотя наряду с этим в подгруппах не было выявлено достоверных эффектов, связанных с серологическим статусом и возрастом (набор детей не проводился). Так как все пациенты были невакцинированными, а рандомизация проведена в течение 5 дней от момента появления симптомов, и дополнительных лечебных мероприятий не осуществлялось, проведение указанных видов анализа в подгруппах было невозможным. Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие комбинации нирматрелвира и ритонавира Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней Отношение шансов 0,04 (95% ДИ: 0–0,67) на основании данных о 3100 участниках в 2 исследованиях (рандомизированные контролируемые) 6 на 1000 0 на 1000 Низкая ввиду существенной неоднозначности трактовки и косвенного характера данных1 Комбинация нирматрелвира и ритонавира может оказывать слабое воздействие на показатель смертности Разница: сокращение на 6 случаев на 1000 (95% ДИ: сокращение на 6 случаев – сокращение на 2 случая) Искусственная вентиляция легких Нет данных Влияние комбинации нирматрелвира и ритонавира не определено. Госпитализация Риск в исследованиях Отношение шансов 0,15 (95% ДИ: 0,06– 0,38) на основании данных о 3078 участниках в 2 исследованиях (рандомизированные контролируемые) 35 на 1000 5 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных2 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 30 случаев на 1000 (95% ДИ: сокращение на 33 случая – сокращение на 21 случай) 31 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие комбинации нирматрелвира и ритонавира Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Госпитализация Группа высокого риска Отношение шансов 0,15 (95% ДИ: 0,06– 0,38) на основании данных о 3078 участниках в 2 исследованиях (рандомизированные контролируемые) 60 на 1000 9 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных3 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 51 случай на 1000 (95% ДИ: сокращение на 56 случаев – сокращение на 36 случаев) Госпитализация Группа наивысшего риска Отношение шансов 0,15 (95% ДИ: 0,06– 0,38) на основании данных о 3078 участниках в 2 исследованиях (рандомизированные контролируемые) 100 на 1000 16 на 1000 Средняя Ввиду вероятности систематической ошибки и неоднозначности трактовки данных4 Предположительно, применение комбинации нирматрелвира и ритонавира способствует сокращению сроков госпитализации Разница: сокращение на 84 случая на 1000 (95% ДИ: сокращение на 93 случая – сокращение на 59 случаев) Нежелательные явления, приводящие к отмене препарата Отношение шансов 0,48 (95% ДИ: 0,29– 0,8) на основании данных о 2246 участниках в 1 исследовании (рандомизированные контролируемые) 0 на 1000 0 на 1000 Высокая На фоне приема комбинации нирматрелвира и ритонавира наблюдается минимальный или нулевой риск развития нежелательных явлений, приводящих к отмене препарата Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Время до исчезновения симптомов Нет данных Влияние комбинации нирматрелвира и ритонавира не определено. 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. Применение комбинации нирматрелвира и ритонавира предположительно приводит к снижению смертности у данных пациентов. Неоднозначность трактовки данных: существенная. Общее количество событий составило всего 12 (все в группе плацебо); данные всего одного исследования. 2. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 3. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 4. Риск систематической ошибки: существенный. Сроки завершения исследования были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 32 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: комбинация нирматрелвира и ритонавира Сравнение: молнупиравир Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней Отношение шансов 0 (95% ДИ: 0–0,29) (рандомизированные контролируемые) 0 на 1000 0 на 1000 Средняя Ввиду крайне косвенного характера данных1 Предположительно, влияние на показатель смертности минимально или отсутствует Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Искусственная вентиляция легких Нет данных Влияние комбинации нирматрелвира и ритонавира не определено Госпитализация Риск в исследованиях Отношение шансов 0,29 (95% ДИ: 0,1–0,88) (рандомизированные контролируемые) 19 на 1000 6 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных2 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 13 случаев на 1000 (95% ДИ: сокращение на 17 случаев – сокращение на 2 случая) Госпитализация Группа наивысшего риска Отношение шансов 0,29 (95% ДИ: 0,1–0,88) (рандомизированные контролируемые) 57 на 1000 17 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных3 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 40 случаев на 1000 (95% ДИ: сокращение на 51 случай – сокращение на 6 случаев) Госпитализация Группа крайне высокого риска Отношение шансов 0,29 (95%ДИ: 0,1–0,88) (рандомизированные контролируемые) 33 на 1000 17 на 1000 Низкая Ввиду риска систематической ошибки и неоднозначности трактовки данных4 Применение комбинации нирматрелвира и ритонавира, вероятно, способствует сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 40 случаев на 1000 (95% ДИ: сокращение на 51 случай – сокращение на 6 случаев) 33 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство комбинация нирматрелвира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Нежелательные явления, приводящие к отмене препарата 0 на 1000 0 на 1000 Высокая Различия по критерию риска нежелательных явлений, приводящих к отмене препарата, минимальны или не выявлены. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – сокращение на 0 случаев) Время до исчезновения симптомов Нет данных Влияние нирматрелвира/ ритонавира не определено 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. 2. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 3. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. 4. Риск систематической ошибки: существенный. Сроки завершения исследования комбинации нирматрелвира и ритонавира были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: ремдесивир Сравнение: комбинация нирматрелвира и ритонавира Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство: ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней 0 на 1000 3 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки, косвенным характером данных и неоднозначностью их трактовки1 Влияние на смертность не определено Разница: увеличение на 3 случая на 1000 увеличение на 2 случая – увеличение на 5 случаев Искусственная вентиляция легких Нет данных Влияние на снижение потребности в искусственной вентиляции легких остается неопределенным 34 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство: ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Госпитализация Риск в исследованиях Отношение шансов 1,64 (95%ДИ: 0,33–7,57) (рандомизированные контролируемые) 6 на 1000 9 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки2 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 3 случая на 1000 (95% ДИ: сокращение на 4 случая – увеличение на 38 случаев) Поступление в стационар Крайне высокий риск Отношение шансов 1,64 (95%ДИ: 0,33–7,57) (рандомизированные контролируемые) 9 на 1000 15 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки3 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 55 случаев) Поступление в стационар Наивысший риск Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 16 на 1000 26 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки4 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 10 случаев на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 94 случая) Нежелательные явления, приводящие к отмене препарата 0 на 1000 9 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных, высокой вероятности систематической ошибки, крайне косвенного характера данных и крайне высокого риска систематической ошибки5 Влияние на развитие нежелательных явлений, приводящих к отмене препарата, не определено Время до исчезновения симптомов Нет данных Влияние комбинации нирматрелвира и ритонавира не определено 1. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. Неоднозначность трактовки данных: существенная. Небольшое количество событий: всего 50 событий в сравнении ремдесивир – контроль и 11 событий в сравнении молнупиравир – контроль. 2. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 3. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 4. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 5. Риск систематической ошибки: крайне высокий. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. 35 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.4.1. Механизм действия Нирматрелвир ингибирует протеазу вируса SARS-CoV-2 (3CLpro), тем самым предупреждая расщепление вирусного полипротеина, который необходим для функционирования вирусных белков (32). Ингибирование протеазы не позволяет вирусу реплицироваться. Нирматрелвир вводят совместно с ритонавиром, ингибитором протеаз ВИЧ, который в данной ситуации применяется для улучшения фармакокинетики нирматрелвира и самостоятельно не оказывает непосредственного противовирусного действия. Таким образом, данная комбинация должна рассматриваться как противовирусная монотерапия. Нирматрелвир был разработан как средство для приема внутрь, являющееся аналогом пролекарства с внутривенным путем введения (луфотрелвир; PF-07304814). Данный препарат создавался для лечения инфекции, вызванной вирусом SARS-CoV, и впоследствии был перепрофилирован для лечения инфекции SARS-CoV-2. Показана противовирусная активность нирматрелвира в отношении вируса SARS-CoV-2 в дифференцированных нормальных клетках эпителия бронхов человека с EC50 на уровне 0,06 микромоль и EC90 на уровне 0,18 микромоль (33). После введения комбинации нирматрелвира и ритонавира здоровым добровольцам в дозировке 300/100 мг максимальная концентрация нирматрелвира в плазме составила 2210 нг/мл, период полувыведения составил 6 часов, тогда как фармакокинетические параметры равновесного состояния достигались на второй день (34) (значение параметра EC90 на уровне 0,18 микромоль соответствует примерно 90 нг/мл). При использовании высоких доз (300 мг/кг) нирматрелвира без фармакокинетического усилителя наблюдалась активность в отношении вируса SARS-CoV-2, адаптированного к мышам, вместе с тем максимальные концентрации были выше, чем достигавшиеся у человека при введении дозы 300/100 мг здоровым добровольцам (33). Кроме того, эффективность высоких доз (250 мг/кг) нирматрелвира без фармакокинетического усилителя наблюдалась у переднеазиатских хомяков, зараженных вирусом SARS-CoV-2, однако сведений о фармакокинетике у данного вида животных не имеется (35). Исходя из генетической последовательности варианта «омикрон», молекулярных основ для утраты активности не имеется. Нирматрелвир сохраняет активность в отношении варианта ВА.1 «омикрон» в условиях in vitro (36), однако данных in vivo в настоящее время не имеется. Для оценки скорости возникновения резистентности к нирматрелвиру необходим существенно больший объем данных. Одиночные аминокислотные замены в последовательности протеазы могут привести к 23,6–39-кратному снижению активности нирматрелвира (34). На фоне давления естественного отбора в условиях in vitro вирус гепатита мышей (используемый в качестве суррогата бетакоронавируса) приобрел ряд мутаций, которые приводили к 4–91-кратному снижению активности нирматрелвира (34). В контексте клинических испытаний описаны две аминокислотные замены, одна из которых не влияла на активность нирматрелвира. Ритонавир влияет на метаболизм и выведение других препаратов и обусловливает многочисленные лекарственные взаимодействия, что требует повышенного внимания. Небольшая продолжительность терапии при COVID-19, вероятно, позволяет лучше контролировать лекарственные взаимодействия, чем лечение ВИЧ, вместе с тем режим применения два раза в сутки означает, что пациент получает вдвое большую дозировку ритонавира, чем в большинстве современных схем антиретровирусной терапии. Кроме того, влияние ритонавира на метаболизм может продолжаться в течение нескольких дней после окончания приема. Инструмент проверки лекарственных взаимодействий, разработанный университетом Ливерпуля, может стать ценным средством для контроля взаимодействия других препаратов с комбинацией нирматрелвира и ритонавира. 36 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.5. Ремдесивир (опубликовано 22 апреля 2022 г.) Справочная информация Двадцатого ноября 2020 г. была сделана первоначальная условная рекомендация, согласно которой использование ремдесивира не рекомендовалось пациентам с COVID-19 независимо от тяжести заболевания. Основой для данной рекомендации стали четыре доступных в то время РКИ с участием 7333 человек, госпитализированных в связи с COVID-19. В десятой версии руководящих указаний была сделана новая рекомендация в пользу применения ремдесивира для пациентов с нетяжелым течением заболевания, тогда как рекомендация для пациентов с тяжелым и крайне тяжелым течением COVID-19 находится в разработке и в скором времени будет обновлена. В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся ремдесивира, внесено не было. Для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации Практические сведения Пути введения, дозировка и продолжительность применения. Дополнительные соображения изложены в трех резюме практических вопросов (ремдесивир при COVID-19, прием ремдесивира при COVID-19, безопасность и мониторинг пациентов, получающих ремдесивир для лечения COVID-19 – только на английском языке). Ниже кратко обобщены основные положения. • По данным масштабных исследований, которые были положены в основу этой рекомендации и в которых изучалась схема лечения, рекомендуется применение внутривенного раствора ремдесивира один раз в сутки на протяжении трех дней. Ремдесивир вводят внутривенно в дозе 200 мг в первый день, затем в дозе 100 мг внутривенно во второй и третий дни. • Применение препарата на фоне заболевания необходимо начинать как можно раньше. В исследованиях, которые были рассмотрены, применение ремдесивира начинали в течение 7 дней от дебюта заболевания. • Представляется целесообразным непродолжительное наблюдение за состоянием пациента сразу после инфузии. Любые работники здравоохранения, выполняющие инфузии, должны соблюдать рекомендованные меры профилактики инфекций и инфекционного контроля для амбулаторных условий. • У пациентов с выраженными нарушениями функции печени или почек необходимо применять ремдесивир с осторожностью. • Группа по разработке руководящих принципов отметила, что в исследовании не участвовали дети в возрасте до 12 лет включительно с массой тела менее 40 кг, в связи с чем применение препарата в этой группе пациентов не рекомендуется. • Кроме того, в исследовании не участвовали беременные или кормящие женщины. Решение касательно использования данного лекарственного средства должно приниматься беременной женщиной и ее лечащим врачом с учетом соотношения потенциальной пользы и возможного риска для матери и плода (см. раздел, посвященный данным по итогам исследования, а также Информационный листок ВОЗ). Условная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием ремдесивира (настоятельная рекомендация в пользу применения). • Информация для содействия выявлению пациентов, затронутых наивысшим риском госпитализации, содержится в разделе 6.1. • Доступен ряд вариантов лечения: см. инструмент содействия принятию решений, в котором представлены сведения о пользе и вреде применения комбинации нирматрелвира и ритонавира, молнупиравира, ремдесивира и моноклональных антител. • Группа по разработке руководящих принципов пришла к выводу о том, что комбинация нирматрелвира и ритонавира является наилучшим вариантом лечения, так как данные средства, вероятно, обладают большей эффективностью в отношении профилактики госпитализации по сравнению с альтернативами, обладают меньшим количеством эффектов, вызывающих обеспокоенность, по сравнению с молнупиравиром и более удобны при приеме по сравнению с ремдесивиром или антителами, требующими внутривенного введения. • Применение ремдесивира должно начинаться как можно раньше от момента появления симптомов, в идеальном случае в течение 7 дней. 37 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Применение ремдесивира у пациентов с нетяжелым течением COVID-19 предположительно приводит к снижению риска госпитализации и сокращению времени до исчезновения симптомов и предположительно оказывает слабое или нулевое влияние на показатель смертности. Влияние ремдесивира на потребность в искусственной вентиляции легких и время до исчезновения симптомов остается крайне неопределенным. Лечение предположительно не приводит к повышению вероятности нежелательных эффектов, вызывающих отмену лекарственного препарата. Соотношение между преимуществами и возможным вредом указывает в пользу лечения, однако лишь в группе наивысшего риска. Это связано с тем, что абсолютная польза ремдесивира при госпитализации зависит от прогноза данного пациента. Группой по разработке руководящих принципов установлено, что абсолютное сокращение количества госпитализаций на уровне 6% представляет собой пороговое значение, которое будет рассматриваться большинством людей в качестве важного преимущества. На фоне применения ремдесивира данная величина будет достигаться в группе пациентов с наивысшим риском госпитализации (исходный риск выше 10%), например среди пожилых или людей с иммунодефицитами и / или хроническими заболеваниями, для которых отсутствие вакцинации будет являться дополнительным отягощающим фактором. Условная рекомендация применять ремдесивир в группах наивысшего риска (исходный риск выше 10%) отражает следующую пороговую величину: сокращение количества госпитализаций на 73 на 1000 пациентов. Проведение планового сравнительного анализа в подгруппах для ремдесивира и стандарта оказания помощи, в том числе по критериям возраста, времени появления симптомов и тяжести заболевания, было невозможным ввиду отсутствия опубликованных либо предоставленных исследователями данных в подгруппах. В исследовании PINETREE (37) приняли участие восемь детей (12 лет и старше); вместе с тем случаев летального исхода или госпитализации не имелось. Убедительность фактических данных В основу резюме фактических данных было положено пять исследований, включенных в ОДСМА, с участием 2709 человек, в том числе одно исследование исходов госпитализации (1)(37). Оценка степени убедительности фактических данных: средняя в отношении сокращения объема госпитализации (понижена ввиду существенной неоднозначности трактовки данных); низкая в отношении показателя смертности (ввиду существенной неоднозначности трактовки и косвенного характера данных); крайне низкая в отношении искусственной вентиляции легких (ввиду чрезвычайно высокой степени неоднозначности трактовки данных и высокого риска систематической ошибки); средняя в отношении нежелательных эффектов, приводящих к отмене лекарственного препарата. Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных ввиду их косвенного характера, обусловленного главным образом ограниченной доступностью разработанного эмпирическим путем метода прогнозирования риска, позволяющего определять риск госпитализации у отдельных пациентов (18)(31). Подробные сведения см. в разделе 6.1. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что почти все надлежащим образом информированные пациенты с низким риском госпитализации будут склонны отказаться от применения ремдесивира, и только пациенты из группы наивысшего риска предпочтут получить данное лечение. Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Ремдесивир вводят один раз в сутки внутривенно каждый день в течение 3 дней подряд, что является трудностью для амбулаторных пациентов, которые стремятся избежать госпитализации. Кроме того, что лечение ремдесивиром, по- видимому, не будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Данный факт подчеркивает необходимость создания запасов ремдесивира для лиц, находящихся в группе наивысшего риска. Недостаточная представленность данного средства в СНСД, обусловленная стоимостью, практическими трудностями и физической доступностью, вызывает обеспокоенность (38). Кроме того, в СНСД могут более остро проявляться трудности совместного принятия решений и информирования о вреде и пользе ремдесивира. Например, доступ к услугам, в том числе диагностическому тестированию и лечению, в первые семь дней от момента появления симптомов нередко бывает затруднен для лиц, находящихся в неблагоприятном социально-экономическом положении, что, в свою очередь, ограничивает доступность вмешательств. Таким образом, выполнение вмешательства у пациентов с наивысшим риском может обострять неравенство в области здравоохранения. В масштабе стран важно интегрировать схему маршрутизации лиц с COVID-19 в механизм обслуживания пациентов с нетяжелым течением COVID-19 (то есть в систему первичной медико-санитарной помощи или общинные учреждения). 38 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Данные рекомендации должны обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этому средству лечения. Одним из примеров служит опубликованное 17 декабря 2021 г. Восьмое приглашение ВОЗ для производителей лекарственных средств для лечения COVID-19 к подаче предварительных заявок на участие в оценке продукции в Департамент преквалификации ВОЗ. В случае, если по итогам такой оценки будет установлено соответствие средства и производителя (а также клинической базы) требованиям стандартов, рекомендованных ВОЗ, средство будет включено в перечень медицинской продукции, одобренной для закупок организациями системы ООН и другими участниками. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Доступ к диагностическим средствам для выявления вируса SARS-CoV-2. Так как в данной рекомендации подчеркнута необходимость проведения лечения ремдесивиром в течение 7 дней с момента появления симптомов, важнейшее значение имеет расширение доступа и обеспечение надлежащего использования диагностических тестов. В этой связи для улучшения доступа к лекарственным средствам, особенно тем, которые применимы в ранний период заболевания, необходимо наличие и использование надежных и своевременных диагностических тестов для определения вируса SARS- CoV-2 (в том числе на основе метода амплификации нуклеиновых кислот (МАНК), а также диагностических экспресс-тестов на определение антигенов (АГ-ДЭТ)). Надлежащее использование АГ-ДЭТ населением и квалифицированными специалистами может улучшить раннюю диагностику и своевременный доступ к клинической помощи, особенно в общинных учреждениях и учреждениях первичной медико-санитарной помощи. Национальные программы должны оптимизировать системы тестирования с учетом эпидемической обстановки на местах, целей ответных мер, доступных ресурсов и потребностей местного населения. Обоснование При вынесении на основании фактических данных условной рекомендации использовать ремдесивир у пациентов с нетяжелой формой COVID-19 группа подчеркнула пользу данного препарата, проявляющуюся в снижении потребности в госпитализации, а также полное или почти полное отсутствие серьезных побочных эффектов на фоне применения. Кроме того, были тщательно рассмотрены вопросы практического использования и удобства введения препарата, в связи с чем была сделана рекомендация в пользу применения только в группе пациентов наивысшего риска. К типичным характеристикам лиц, затронутых наивысшим риском, относятся пожилой возраст, наличие иммунодефицитных состояний и/или хронических заболеваний, а также отсутствие вакцинации, что дополнительно усугубляет риск. К числу важных соображений относятся аспекты, связанные со стоимостью и обеспечению доступности, и группа признает, что данная рекомендация может обострить неравенство в вопросах здоровья. Группа по разработке руководящих принципов исходила из предположения о том, что среди пациентов не будет выявлено существенных различий ценностных ориентиров и предпочтений (см. раздел, посвященный фактическим сведениям, лежащим в основе данного решения). Альтернативы, а также комбинированные средства лечения Ранее группа по разработке руководящих принципов вынесла условную рекомендацию в пользу применения молнупиравира в группе пациентов с нетяжелым течением заболевания, затронутых наивысшим риском, а также, в рамках данного документа, настоятельную рекомендацию в пользу применения комбинации нирматрелвира и ритонавира (см. раздел 6.2) и условную рекомендацию против применения комбинации нирматрелвира и ритонавира в группе пациентов низкого риска с нетяжелым течением заболевания. При косвенном сравнении в группах крайне высокого и наивысшего риска было установлено, что прием ремдесивира может способствовать большему сокращению продолжительности госпитализации, чем прием молнупиравира (низкая степень убедительности); вместе с тем такие различия были минимальными или нулевыми при сравнении с приемом комбинации нирматрелвира и ритонавира (низкая степень убедительности). В отсутствие непосредственных данных, а также в связи с низкой степенью убедительности косвенных сравнений группа предпочла не выносить сравнительные рекомендации в отношении различных препаратов; вместо этого сделано указание на то, что комбинация нирматрелвира и ритонавира может быть более предпочтительной в связи с большей эффективностью, чем стандарт оказания помощи, а окончательный выбор должен определяться практическими соображениями, такими как простота введения и возможные лекарственные взаимодействия. Фактических данных в пользу комбинированного использования других противовирусных препаратов не имеется, в связи с чем данный подход группой не рекомендован. Возможность применения Только в одном из рассмотренных исследований принимали участие дети (в возрасте 12 лет и старше), и их количество было крайне небольшим; в этой связи применимость данной рекомендации к детям остается невыясненной. Кроме того, остается неопределенность в отношении использования ремдесивира у беременных и кормящих женщин. Решение касательно использования данного лекарственного средства должно приниматься беременной женщиной и ее лечащим врачом с учетом соотношения потенциальной пользы и возможного риска для матери и плода (см. вкладки «Данные по итогам исследования» и «Практические сведения»). Кроме того, группа по разработке руководящих принципов выразила озабоченность в отношении сохранения эффективности препарата против вновь появляющихся вариантов вируса, вызывающих обеспокоенность, таких как вариант «омикрон» BA.1 или BA.2. Необходимо проведение эпиднадзора за штаммами вируса SARS-CoV-2 со сниженной восприимчивостью к ремдесивиру, а также дальнейших исследований по изучению роли комбинированной терапии у пациентов с тяжелым иммунодефицитом. До поступления дополнительных сведений не имеется оснований предполагать снижение активности в отношении известных в настоящее время вариантов вируса. 39 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: ремдесивир Сравнение: комбинация нирматрелвира и ритонавира Исход Период времени Результаты исследования и количественные показатели Сравнение комбинация нирматрелвира и ритонавира Вмешательство: ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность в течение 28 дней 0 на 1000 3 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки, косвенным характером данных и неоднозначностью их трактовки1 Влияние на смертность не определено Разница: увеличение на 3 случая на 1000 увеличение на 2 случая – увеличение на 5 случаев Искусственная вентиляция легких Нет данных Влияние на потребность в искусственной вентиляции легких остается неопределенным Госпитализация Риск в исследованиях Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 6 на 1000 9 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки2 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 3 случая на 1000 (95% ДИ: сокращение на 4 случая – увеличение на 38 случаев) Поступление в стационар Крайне высокий риск Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 9 на 1000 15 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки данных3 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 55 случаев) Поступление в стационар Наивысший риск Отношение шансов 1,64 (95% ДИ: 0,33–7,57) (рандомизированные контролируемые) 16 на 1000 26 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки данных4 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: увеличение на 10 случаев на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 94 случая) Нежелательные явления, приводящие к отмене препарата 0 на 1000 9 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных, высокой вероятности систематической ошибки, крайне косвенного характера данных и крайне высокого риска систематической ошибки5 Влияние на развитие нежелательных явлений, приводящих к отмене препарата, не определено Время до исчезновения симптомов Нет данных Влияние комбинации нирматрелвира и ритонавира не определено 40 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. Неоднозначность трактовки данных: существенная. Небольшое количество событий: всего 50 событий в сравнении ремдесивир – контроль и 11 событий в сравнении молнупиравир – контроль. 2. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 3. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 4. Риск систематической ошибки: существенный. Сроки завершения исследования EPIC-HR, в котором сравнивали комбинацию нирматрелвира и ритонавира, были чрезвычайно сжатыми для определения преимуществ. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область отсутствия преимуществ, так и существенного вреда. 5. Риск систематической ошибки: крайне высокий. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: ремдесивир Сравнение: отсутствие терапии ремдесивиром Резюме В основу ОДСМА для ремдесивира были положены пять РКИ с участием 2731 пациента с нетяжелым течением заболевания в амбулаторных условиях; были доступны данные по 2710 пациентам. Все РКИ были зарегистрированы; в рецензируемых журналах опубликованы четыре из них (15)(37)(39)(40). В одном из рассмотренных исследований принимали участие дети в возрасте 12 лет и старше; ни в одном из исследований не участвовали беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения ремдесивира по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (3). Исследование PINETREE было единственным, в котором информация о подгруппе пациентов с нетяжелым течением заболевания была представлена в подробной разбивке (37). Возможность выполнения планового анализа в подгруппах была ограничена доступностью данных, хотя наряду с этим в подгруппах не было выявлено достоверных эффектов, связанных с серологическим статусом и возрастом. Так как все пациенты были невакцинированными, рандомизация была проведена в течение 7 дней от момента появления симптомов, а дополнительных лечебных мероприятий не осуществлялось, выполнение указанных видов анализа в подгруппах было невозможным. Применительно к возрасту пациентов следует заметить, что возраст 1,4% (n=8) участников исследования PINETREE составлял от 12 до 18 лет , среди этих пациентов не было зарегистрировано случаев летального исхода или госпитализации; эффекта в подгруппах для лиц в возрасте > 60 и ≤ 60 лет (p=0,78) не наблюдалось. Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие терапии ремдесивиром Вмешательство: ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов 0,68 (95% ДИ: 0,39–1,21) на основании данных о 2709 участниках в 5 исследованиях (рандомизированные контролируемые) 6 на 1000 4 на 1000 Низкая Ввиду крайне косвенного характера данных и неоднозначности их трактовки1 Вероятно, ремдесивир оказывает слабое влияние, либо не оказывает влияние на показатель смертности Разница: сокращение на 2 случая на 1000: сокращение на 4 случая – увеличение на 1 случай 41 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение отсутствие терапии ремдесивиром Вмешательство: ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Искусственная вентиляция легких Отношение шансов 0,42 (95% ДИ: 0,08–1,96) на основании данных о 261 участнике в 2 исследованиях (рандомизированные контролируемые) 8 на 1000 3 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных и их чрезвычайно косвенного характера2 Влияние ремдесивира на вентиляцию легких не определено Разница: сокращение на 5 случаев на 1000 (95% ДИ: сокращение на 7 случаев – увеличение на 8 случаев) Госпитализация Риск в исследованиях Отношение шансов 0,25 (95% ДИ: 0,06–0,88) на основании данных о 562 участниках в 1 исследовании (рандомизированные контролируемые) 35 на 1000 9 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Применение ремдесивира предположительно способствует сокращению сроков госпитализации Разница: сокращение на 26 случаев на 1000 (95% ДИ: сокращение на 33 случая – сокращение на 4 случая) Госпитализация Группа высокого риска Отношение шансов 0,25 (95% ДИ: 0,06–0,88) на основании данных о 562 участниках в 1 исследовании (рандомизированные контролируемые) 60 на 1000 16 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных4 Применение ремдесивира предположительно способствует сокращению сроков госпитализации Разница: сокращение на 44 случая на 1000 (95% ДИ: сокращение на 56 случаев – сокращение на 7 случаев) Госпитализация Группа наивысшего риска Отношение шансов 0,25 (95% ДИ: 0,06–0,88) на основании данных о 562 участниках в 1 исследовании (рандомизированные контролируемые) 100 на 1000 27 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных5 Применение ремдесивира предположительно способствует сокращению сроков госпитализации Разница: сокращение на 73 случая на 1000 (95% ДИ: сокращение на 93 случая – сокращение на 11 случаев) Нежелательные явления, приводящие к отмене препарата На основании данных по 1379 пациентам в 4 исследованиях. (рандомизированные контролируемые) 0 на 1000 9 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных6 Различия по критерию нежелательных явлений, приводящих к отмене препарата, предположительно являются минимальными или не выявлены Разница: увеличение на 9 случаев на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 21 случай) Время до исчезновения симптомов Меньший показатель предпочтителен На основании данных по 138 участникам в 1 исследовании (рандомизированные контролируемые) 9 дней (медианное значение) 7,2 дня (среднее значение) Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных7 Влияние применения ремдесивира на время до клинического улучшения состояния не определено Разница: СР на 1,8 меньше (95% ДИ: меньше на 5,7 дня – больше на 3,5 дня) 42 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. Неоднозначность трактовки данных: существенная. Не соответствует оптимальному объему информации; малое количество событий (всего 50). 2. Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. У данных пациентов может иметь место важное различие в показателях перевода на искусственную вентиляцию легких. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. Не соответствует оптимальному объему информации; малое количество событий (всего 11). 3. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации; малое количество событий (всего 23). 4. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации; малое количество событий (всего 23). 5. Неоднозначность трактовки данных: существенная. Общий размер выборки не отвечает критерию оптимального объема информации; малое количество событий (всего 23). 6. Неоднозначность трактовки данных: существенная. 7. Неоднозначность трактовки данных: крайняя. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: ремдесивир Сравнение: молнупиравир Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство Ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов 6,55 (95% ДИ: 1,3–53,23) (рандомизированные контролируемые) 0 на 1000 0 на 1000 Низкая Ввиду крайне косвенного характера данных и неоднозначности их трактовки1 Вероятно, влияние на смертность минимально или отсутствует Разница: сокращение на 0 случаев на 1000 (95% ДИ сокращение на 0 случаев – сокращение на 0 случаев) Искусственная вентиляция легких Отношение шансов 1,08 (95% ДИ: 0,12–9) (рандомизированные контролируемые) 8 на 1000 9 на 1000 Низкая Ввиду высокой вероятности систематической ошибки, неоднозначности трактовки и косвенного характера данных2 Вероятно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует Разница: увеличение на 1 случай на 1000 (95% ДИ: сокращение на 13 случаев – увеличение на 16 случаев) Госпитализация Риск в исследованиях Отношение шансов 0,48 (95% ДИ: 0,11–1,93) (рандомизированные контролируемые) 19 на 1000 9 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Вероятно, влияние на поступление в стационар минимально или отсутствует Разница: сокращение на 10 случаев на 1000 (95% ДИ: сокращение на 17 случаев – увеличение на 17 случаев) Госпитализация Группа высокого риска Отношение шансов 0,48 (95% ДИ: 0,11–1,93) (рандомизированные контролируемые) 33 на 1000 16 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных4 Вероятно, применение ремдесивира может способствовать сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 17 случаев на 1000 (95% ДИ: сокращение на 29 случаев – увеличение на 29 случаев) Госпитализация Группа наивысшего риска Отношение шансов 0,48 (95% ДИ: 0,11–1,93) (рандомизированные контролируемые) 57 на 1000 28 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных5 Вероятно, применение ремдесивира может способствовать сокращению госпитализации на более продолжительные сроки, чем применение молнупиравира Разница: сокращение на 29 случаев на 1000 (95% ДИ: сокращение на 50 случаев – увеличение на 47 случаев) 43 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение молнупиравир Вмешательство Ремдесивир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Нежелательные явления, приводящие к отмене препарата 0 на 1000 9 на 1000 Крайне низкая Ввиду высокой вероятности систематической ошибки, неоднозначности трактовки и косвенного характера данных6 Влияние на развитие нежелательных явлений, приводящих к отмене препарата, не определено Разница: увеличение на 9 случаев на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 21 случай) Время до исчезновения симптомов Меньший показатель предпочтителен (рандомизированные контролируемые) 5,6 дня (медианное значение) 7,9 дня (среднее значение) Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных7 Влияние на время до исчезновения симптомов остается крайне неопределенным Разница: СО: на 2,3 больше (ДИ 95% на 1,9 дня меньше – на 7,8 дня больше) 1. Косвенный характер данных: существенный. Ряд пациентов может быть затронут существенно более высоким риском летального исхода. У данных пациентов может иметь место важное различие в показателях смертности. Неоднозначность трактовки данных: существенная. Небольшое количество событий: всего 50 событий в сравнении ремдесивир – контроль и 11 событий в сравнении молнупиравир – контроль. 2. Риск систематической ошибки: существенный. Фактические данные в пользу применения молнупиравира характеризуются высоким риском систематической ошибки. Косвенный характер данных: существенный. Ряд пациентов может быть затронут крайне высоким риском перевода на искусственную вентиляцию легких. У данных пациентов может иметь место важное различие в показателях перевода на искусственную вентиляцию легких. 3. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. 4. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. 5. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. 6. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 7. Неоднозначность трактовки данных: крайняя. 6.5.1. Механизм действия Ремдесивир был разработан для лечения вирусного гепатита С, и, кроме того, его применение изучалось при болезнях, вызванных вирусами Эбола и Марбург, помимо этого, препарат был перепрофилирован для лечения инфекции SARS-CoV-2. Ремдесивир является нуклеозидным препаратом. Механизм его действия основан на обрыве цепи, что отличается от летального мутагенеза: в ходе репликации РНК-генома полимераза вируса SARS-CoV-2 активно встраивает молекулы препарата вместо эндогенных аденозиновых нуклеозидов. В отличие от многих других нуклеозидных препаратов, механизм действия которых основан на обрыве цепи, ремдесивир приводит к терминации синтеза РНК в отсроченном периоде, так как обрыв происходит после добавления трех дополнительных нуклеотидов, а не в точке встраивания молекулы ремдесивира (41). Возникновение лекарственной устойчивости вируса. На фоне давления естественного отбора в условиях in vitro отмечено возникновение лекарственной устойчивости вируса SARS-CoV-2 к ремдесивиру, что связывают с мутацией (E802D) в последовательности, кодирующей полимеразу (42). Кроме того, мутация E802D описана в клиническом случае, в котором у пациента с ослабленным иммунитетом, получавшего лечение ремдесивиром, после периода вирусологического ответа на лечение было выявлено возобновление активного вирусовыделения (43). Клиническая значимость данных наблюдений в случае широкого применения ремдесивира в амбулаторном звене не установлена. 44 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.6. Молнупиравир (опубликовано 3 марта 2022 г.) Справочная информация Рекомендации по применению молнупиравира для лечения пациентов с нетяжелым течением COVID-19 были опубликованы 3 марта 2022 г. в девятой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Рекомендации были выпущены в рамках ОДСМА, посвященного лекарственной терапии, после опубликования результатов шести РКИ (1). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся молнупиравира, внесено не было. Для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации (за исключением беременных и кормящих женщин, а также детей) Практические сведения Пути введения, дозировка и продолжительность применения. Дополнительные соображения изложены в трех резюме практических вопросов (молнупиравир при COVID-19, прием молнупиравира при COVID-19, безопасность и мониторинг пациентов, получающих молнупиравир для лечения COVID-19 – только на английском языке). Ниже кратко обобщены основные положения. • По данным масштабных исследований, которые были положены в основу этой рекомендации и в которых изучалась схема лечения, рекомендуется применение молнупиравира по одной таблетке 800 мг каждые 12 часов на протяжении 5 дней подряд. • Применение препарата на фоне заболевания необходимо начинать как можно раньше. В исследованиях, которые были рассмотрены, применение молнупиравира начинали в течение 5 дней от дебюта заболевания. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Применение молнупиравира у пациентов с нетяжелым течением COVID-19, вероятно, приводит к снижению риска госпитализации и сокращению времени до исчезновения симптомов и может приводить к снижению смертности. Влияние молнупиравира на потребность в искусственной вентиляции легких остается крайне неопределенным. Лечение не приводит к повышению вероятности нежелательных эффектов, вызывающих отмену лекарственного препарата. Вместе с тем данных о вероятном долгосрочном вреде применения молнупиравира не получено, что вызывает обеспокоенность в отсутствие клинических данных. К возможным вредным последствиям относятся возникновение устойчивости, а также вероятный вред, вызванный риском мутагенеза, индуцированного приемом молнупиравира. Указанные допущения (см. раздел «Обоснование») сделаны на основе механизма действия молнупиравира и имеющихся данных доклинических исследований (см. раздел «Механизм действия»). Условная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием молнупиравира (условная рекомендация в пользу применения) • Информация для содействия выявлению пациентов, затронутых наивысшим риском госпитализации, содержится в разделе 6.1. • Доступен ряд вариантов лечения: см. инструмент содействия принятию решений, в котором представлены сведения о пользе и вреде применения комбинации нирматрелвира и ритонавира, молнупиравира, ремдесивира и моноклональных антител. • В связи с отсутствием клинических данных на уровне пациентов или популяции в целом, отрицательные последствия применения молнупиравира в отсроченном периоде достоверно не установлены. К ним относится генетическая токсичность, возникновение устойчивости и появление новых вариантов вируса (см. «Механизм действия»). • Условный характер рекомендации отражает обеспокоенность широким применением молнупиравира до появления данных о безопасности. • Применение молнупиравира должно сопровождаться реализацией мер снижения вреда, например отказом от применения данного препарата среди молодежи, программами активного фармаконадзора и мониторингом генетических последовательностей вирусной полимеразы и спайк-белка (см. раздел «Обоснование»). 45 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Соотношение преимуществ и возможного вреда практически не позволяет сделать однозначного выбора, за исключением случаев лечения в группе наивысшего риска при условии реализации других мер смягчения вреда на индивидуальном и популяционном уровне (см. раздел «Меры смягчения вреда»). На фоне монотерапии молнупиравиром (или монотерапии любым другим противовирусным средством) имеется риск возникновения лекарственной устойчивости, как было показано в случае с другими противовирусными препаратами (см. раздел «Механизм действия»). Абсолютная польза применения молнупиравира в отношении снижения риска госпитализации определяется прогнозом. Группой по разработке руководящих принципов установлено, что абсолютное сокращение количества госпитализаций на уровне 6% представляет собой пороговое значение, которое будет рассматриваться большинством пациентов в качестве важного преимущества. При лечении молнупиравиром данное преимущество может наблюдаться в группе пациентов, затронутых наивысшим риском госпитализации (исходный риск на уровне более 10%), например среди невакцинированных лиц, пожилых людей или лиц, страдающих иммунодефицитами и/или хроническими заболеваниями. Условная рекомендация применять молнупиравир в указанных группах наивысшего риска отражает следующую пороговую величину: сокращение количества госпитализаций на 60 случаев на 1000 пациентов и более высокий прогнозируемый уровень выживаемости в абсолютном выражении, хотя количественная характеристика в отсутствие данных затруднена. В отсутствие обнародованных или предоставленных исследователями данных в подгруппах планируемый анализ в разбивке по подгруппам не мог быть выполнен. Убедительность фактических данных В основу резюме фактических данных было положено шесть исследований, включенных в ОДСМА, с участием 4796 человек, в том числе исследование MOVe-OUT (44). Оценка степени убедительности фактических данных: средняя в отношении сокращения сроков госпитализации (понижена ввиду существенной неоднозначности трактовки данных); низкая в отношении показателя смертности (понижена ввиду существенной неоднозначности трактовки и косвенного характера данных); средняя в отношении времени до исчезновения симптомов (понижена ввиду высокого риска систематической ошибки); крайне низкая в отношении искусственной вентиляции легких (понижена ввиду чрезвычайно высокой степени неоднозначности трактовки данных и высокого риска систематической ошибки); высокая в отношении нежелательных эффектов, приводящих к отмене лекарственного препарата. Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных ввиду их косвенного характера, обусловленного главным образом ограниченной доступностью разработанного эмпирическим путем метода прогнозирования риска, позволяющего определять риск госпитализации у отдельных пациентов (31). Кроме того, эксперты группы сочли, что косвенный характер данных отчасти обусловлен возможностью появления новых вариантов вируса (в том числе варианта «омикрон»), против которых терапия моноклональными антителами, возможно, будет менее эффективной. Группа приняла решение не понижать оценку степени убедительности данных в связи с неоднозначностью трактовки в условиях, в которых низкая частота событий отражает крайне низкий исходный риск (например, смертность). Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по подготовке руководящих принципов пришли к выводу о том, что почти все надлежащим образом информированные пациенты с низким риском госпитализации будут склонны отказаться от применения молнупиравира, и только пациенты из группы высокого риска (то есть невакцинированные, пожилые, люди с иммунодефицитными состояниями) предпочтут получить данное лечение. В связи с отсутствием научных данных в ходе предыдущего обследования (см. рекомендацию в отношении комбинации казиривимаба и имдевимаба), группа высказала мнение о том, что большинство пациентов с риском госпитализации более 10%, и, соответственно, снижением абсолютного риска примерно на 6%, предпочтут пройти лечение, в то время как большинство пациентов с риском ниже этого уровня будут склонны воздержаться от него. В связи с данной рекомендацией группой было проведено аналогичное обследование; группа выдвинула предположение о том, что большинство пациентов сочтут важным показатель сокращения абсолютного риска летального исхода на уровне 3 на 1000 (повышение количества выздоровевших лиц с 995 до 998 на 1000 пациентов). Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Группа по разработке руководящих принципов отметила низкую вероятность того, что лечение молнупиравиром будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Данный факт подчеркивает необходимость создания запасов молнупиравира для лиц, находящихся в группе наивысшего риска. Вызывает обеспокоенность слабая доступность препарата ввиду его стоимости и дефицита в странах с низким и средним уровнем дохода (СНСД) (38). Кроме того, в СНСД могут более остро проявляться трудности совместного принятия решений и информирования о вреде и пользе молнупиравира. Например, доступ к услугам, в том числе диагностическому тестированию и лечению, в первые пять дней от момента появления симптомов нередко бывает затруднен для лиц, находящихся в неблагоприятном социально-экономическом положении, что, в свою очередь, ограничивает доступность вмешательств. Таким образом, выполнение вмешательства у пациентов с наивысшим риском может обострять неравенство в области здравоохранения. В масштабе стран важно интегрировать схему маршрутизации лиц с COVID-19 в механизм обслуживания пациентов с нетяжелым течением COVID-19 (то есть в систему первичной медико-санитарной помощи или общинные учреждения). 46 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Данные рекомендации должны обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этому средству лечения. Одним из примеров служит опубликованное 17 декабря 2021 г. Седьмое приглашение ВОЗ для производителей лекарственных средств для лечения COVID-19, в том числе молнупиравира, к подаче предварительных заявок на участие в оценке продукции в Департамент преквалификации ВОЗ. В случае, если по итогам такой оценки будет установлено соответствие средства и производителя (а также клинической базы) требованиям стандартов, рекомендованных ВОЗ, средство будет включено в перечень медицинской продукции, одобренной для закупок организациями системы ООН и другими участниками. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Доступ к диагностическим средствам для выявления вируса SARS-CoV-2 Так как в данной рекомендации подчеркнута необходимость проведения лечения молнупиравиром в течение 5 дней с момента появления симптомов, важнейшее значение имеет расширение доступа и обеспечение надлежащего использования диагностических тестов. В этой связи для улучшения доступа к лекарственным средствам, особенно тем, которые применимы в ранний период заболевания, необходимо наличие и использование надежных и своевременных диагностических тестов на COVID-19 (в том числе МАНК и АГ-ДЭТ). Надлежащее использование АГ-ДЭТ населением и квалифицированными специалистами может улучшить раннюю диагностику и своевременный доступ к клинической помощи, особенно в общинных учреждениях и учреждениях первичной медико-санитарной помощи. Национальные программы должны оптимизировать системы тестирования с учетом эпидемической обстановки на местах, целей ответных мер, доступных ресурсов и потребностей местного населения. Обоснование Рассмотренные в совокупности фактические данные, ценностные ориентиры и предпочтения, а также вопросы практического осуществления легли в основу условной рекомендации использовать молнупиравир только у пациентов с нетяжелым течением COVID-19, подвергающихся наиболее высокому риску госпитализации. К типичным характеристикам лиц, затронутых наивысшим риском, могут быть отнесены отсутствие вакцинации, пожилой возраст или наличие иммунодефицитных состояний и/или хронических заболеваний (например, диабета). Вероятно, лишь небольшая доля пациентов – люди, затронутые наивысшим риском, – получат достаточные преимущества, которые превышают возможные риски и другие ограничения и негативные последствия лечения. К таким отрицательным аспектам относятся дефицит надежных инструментов для определения пациентов группы высокого риска, ограниченная доступность лекарственного средства, а также изложенные ниже проблемы в области безопасности. • Группа по разработке руководящих принципов выразила обеспокоенность в связи с риском возникновения устойчивости на фоне применения нового противовирусного средства для монотерапии (см. раздел «Механизм действия»). Существует значительная неопределенность в отношении темпов развития устойчивости; по мнению группы, в отсутствие достаточных клинических данных неопределенность сохраняется. • Касательно риска стимуляции появления новых вариантов вируса в условиях использования препарата группа отметила, что вероятность создания давления естественного отбора, способствующего появлению новых вариантов вируса, на фоне применения препарата низка; вместе с тем в отсутствие достаточных клинических данных сохраняется существенная неопределенность. • В лабораторных экспериментах показано мутагенное действие молнупиравира на клетки млекопитающих, однако данных в пользу мутагенности на моделях животных или человека не выявлено. По этой причине группа по разработке руководящих принципов признала наличие неопределенности в отношении генетической токсичности и риска возникновения злокачественных новообразований в отсроченном периоде в связи с приемом молнупиравира. • Принимая во внимание данные, полученные на модели детенышей крысы, о влиянии приема препарата на толщину ростковой пластинки, молнупиравир не следует применять у детей. Аналогичным образом, в связи с тем, что прием молнупиравира приводил к гибели эмбриона и плода, а также оказывал тератогенное действие на потомство при назначении беременным животным, препарат не следует применять беременным или кормящим женщинам. • Группа по разработке руководящих принципов признала, что мутагенное действие молнупиравира может особенно сильно затрагивать сперматогенез, вместе с тем остается неопределенность в части последствий зачатия детей от мужчин, получающих или недавно закончивших прием молнупиравира. Возможность применения Так как во всех рассмотренных РКИ участвовали взрослые пациенты за исключением беременных, применимость данной рекомендации к детям, кормящим и беременным женщинам остается невыясненной. Вместе с тем, группа пришла к выводу о том, что молнупиравир не следует назначать детям, кормящим или беременным женщинам с COVID-19. Кроме того, в случае планирования семьи мужчины должны быть предупреждены о вероятности временного генотоксического воздействия препарата на сперматогенез (см. раздел «Меры смягчения вреда»). По-видимому, неустановленная вероятность генотоксичности в долгосрочном периоде будет выше для пациентов молодого возраста, в связи с чем применение препарата в данной группе у лиц, не подвергающихся существенному риску, следует избегать. Кроме того, группа выразила озабоченность в отношении сохранения эффективности препарата против вновь появляющихся вариантов вируса, вызывающих обеспокоенность, таких как вариант «омикрон». Хотя на молекулярном уровне отсутствуют факторы снижения эффективности препарата, группа подчеркнула, что повышенная вирусная нагрузка и сопутствующая этому тяжесть течения заболевания могут отрицательно сказаться на эффективности молнупиравира. Принимая во внимание тот факт, что доступные сведения не охватывают пациентов с инфекцией, вызванной новыми вариантами вируса, в том числе вариантом «омикрон», неопределенность в данном вопросе сохраняется (см. раздел 9). 47 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: молнупиравир Сравнение: стандарт оказания помощи Резюме Резюме фактических данных В основу ОДСМА для молнупиравира были положены шесть РКИ с участием 4827 пациентов с нетяжелым течением заболевания, которые находились в амбулаторных условиях; группа по проведению ОДСМА имела доступ к данным по 4796 пациентам. Все РКИ были зарегистрированы; публикаций по данным РКИ в рецензируемых журналах не имеется. Ни в одном из включенных исследований не участвовали дети или беременные женщины. В приложении содержится резюме характеристик исследования и оценка риска систематической ошибки, оценка эффекта по критерию исхода, а также соответствующие лесовидные диаграммы для сравнения молнупиравира со стандартом оказания помощи. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения молнупиравира по сравнению со стандартом оказания помощи для пациентов с нетяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (3). Анализ в подгруппах Группа запросила проведение анализа в пяти заранее определенных подгруппах: 1. Возраст: дети (до 19 лет включительно) по сравнению со взрослыми (20–60 лет) и лицами старшего возраста (60 лет и старше). 2. Тяжесть течения заболевания (на момент начала лечения): нетяжелое по сравнению с тяжелым и крайне тяжелым течением. 3. Время до появления симптомов. 4. Серологический статус (серопозитивные по сравнению с серонегативными). 5. Прививочный статус (невакцинированные по сравнению с вакцинированными). В исследования не проводился набор детей, а также пациентов с тяжелой или крайне тяжелой формой заболевания. Во все исследования проводился набор невакцинированных лиц, продолжительность симптомов заболевания у которых составляла менее 5 дней. Данные, касающиеся серологического статуса, не сообщались. Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство молнупиравир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов 0,06 (95% ДИ: 0–0,4) на основании данных о 4796 участниках в 6 исследованиях (рандомизированные контролируемые) 6 на 1000 0 на 1000 Низкая ввиду существенной неоднозначности трактовки и косвенного характера данных1 Вероятно, применение молнупиравира оказывает слабое воздействие на показатель смертности Разница: сокращение на 6 случаев на 1000 (95% ДИ сокращение на 6 случаев – сокращение на 4 случая) Искусственная вентиляция легких Отношение шансов 1 (95% ДИ: 0,02–59,74) на основании данных о 1220 участниках в 1 исследовании (рандомизированные контролируемые) 8 на 1000 8 на 1000 Крайне низкая Ввиду высокой вероятности систематической ошибки и чрезвычайно высокой степенью неоднозначности трактовки данных2 Влияние молнупиравира на потребность в вентиляции легких остается крайне неопределенным. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 8 случаев – увеличение на 317 случаев) Госпитализация Риск в исследованиях Отношение шансов 0,54 (95% ДИ: 0,3–0,89) на основании данных о 4688 участниках в 5 исследованиях. (рандомизированные контролируемые) 35 на 1000 19 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Применение молнупиравира предположительно приводит к снижению вероятности госпитализации Разница: сокращение на 16 случаев на 1000 (95% ДИ: сокращение на 24 случая – сокращение на 4 случая) 48 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство молнупиравир Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Госпитализация Группа крайне высокого риска Отношение шансов 0,54 (95% ДИ: 0,3–0,89) на основании данных о 4688 участниках в 5 исследованиях (рандомизированные контролируемые) 60 на 1000 33 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных4 Применение молнупиравира предположительно приводит к снижению вероятности госпитализации Разница: сокращение на 27 случаев на 1000 (95% ДИ: сокращение на 41 случай – сокращение на 6 случаев) Госпитализация Группа наивысшего риска Отношение шансов 0,54 (95% ДИ: 0,3–0,89) на основании данных о 4688 участниках в 5 исследованиях (рандомизированные контролируемые) 100 на 1000 57 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных5 Применение молнупиравира предположительно приводит к снижению вероятности госпитализации Разница: сокращение на 43 случая на 1000 (95% ДИ: сокращение на 68 случаев – сокращение на 10 случаев) Нежелательные явления, приводящие к отмене препарата На основании данных по 4796 пациентам в 6 исследованиях (рандомизированные контролируемые) 0 на 1000 0 на 1000 Высокая Различия по критерию нежелательных явлений, приводящих к отмене препарата, минимальны или не выявлены Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 0 случаев – увеличение на 2 случая) Время до исчезновения симптомов Предпочтителен более низкий уровень На основании данных по: 3078 участникам в 3 исследованиях (рандомизированные контролируемые) 9 медианное значение 5,6 среднее значение Средняя Ввиду высокой вероятности систематической ошибки6 Прием молнупиравира предположительно приводит к сокращению продолжительности симптомов заболевания Разница: СР на 3,4 меньше (95% ДИ: меньше на 4,8 дня – меньше на 1,7 дня) Злокачественные новообразования В лабораторных экспериментах, а также исследованиях на животных показана возможность канцерогенеза Крайне низкая Данных о применении у человека с долгосрочным последующим наблюдением не имеется Влияние приема молнупиравира на возникновение злокачественных новообразований не определено 1. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском, однако их выявление затруднено. У этих пациентов применение молнупиравира, вероятно, оказывает существенное влияние на показатель смертности. Неоднозначность трактовки данных: существенная. Имеются данные в общей сложности об 11 событиях (10 в контрольных группах и 1 в группе лечения молнупиравиром). 2. Риск систематической ошибки: существенный. Сведения об искусственной вентиляции легких изложены в одном исследовании, в котором не применялся слепой метод. Неоднозначность трактовки данных: крайняя. Крайне малое число событий, получены чрезвычайно широкие доверительные интервалы, которые накрывают как существенные, так и несущественные эффекты. 3. Неоднозначность трактовки данных: существенная. Верхняя граница доверительного интервала накрывает область слабого и несущественного влияния на госпитализацию (снижение на 4 случая на 1000). 4. Неоднозначность трактовки данных: существенная. Верхняя граница доверительного интервала накрывает область слабого и несущественного влияния на госпитализацию (снижение на 4 случая на 1000). 5. Неоднозначность трактовки данных: существенная. Верхняя граница доверительного интервала накрывает область слабого и несущественного влияния на госпитализацию (снижение на 4 случая на 1000). 6. Риск систематической ошибки: существенный. Во всех трех исследованиях наблюдался высокий риск систематической ошибки в связи с отклонениями от запланированного вмешательства (отсутствие маскировки данных). В одном исследовании наблюдался высокий риск систематической ошибки в связи с вероятно неудовлетворительной маскировкой рандомизации. 49 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Подходы к смягчению вреда для решения проблем в области безопасности Справочная информация Принимая во внимание проблемы безопасности, связанные с использованием молнупиравира (см. раздел «Механизм действия»), ВОЗ признает необходимость снижения рисков как для отдельных пациентов, так и на уровне популяции. При вынесении условной рекомендации учтена одна из таких стратегий: использование вмешательства только в группе пациентов, которые подвергаются высокому риску госпитализации или летального исхода. К типичным характеристикам лиц, затронутых наивысшим риском, относятся пожилой возраст, наличие иммунодефицитных состояний и/или хронических заболеваний (например, диабета), а также отсутствие вакцинации против COVID-19. Подробные сведения в отношении вакцинации против COVID-19 содержатся в рекомендациях ВОЗ на сайте Стратегической консультативной группы экспертов по иммунизации. К другим мерам смягчения вреда относятся перечисленные ниже. • Решения о лечении молнупиравиром должны приниматься на основе коллегиальной модели и при условии, что клиницист хорошо осведомлен о потенциальных преимуществах и вреде терапии и способен разъяснить их пациенту для обеспечения информированного решения. См. раздел «Практическая информация». • Молнупиравир не следует назначать беременным или кормящим женщинам или детям. В случае сомнений в отношении наличия беременности до начала лечения необходимо выполнить тест на беременность. В случае, если стоит вопрос о назначении лечения женщине детородного возраста, необходимо проведение консультирования по вопросу контрацепции в период лечения, а также в течение 4 дней после приема заключительной дозы молнупиравира. • При планировании семьи мужчины должны быть предупреждены о вероятности временного генотоксического воздействия препарата на сперматогенез, и в случае, если мужчина ведет активную половую жизнь с женщиной, ему необходимо рекомендовать использование средств контрацепции в период лечения, а также на протяжении не менее 3 месяцев после приема заключительной дозы молнупиравира (46). • По-видимому, неустановленная вероятность генотокисчности в долгосрочном периоде будет выше для пациентов молодого возраста; в связи с этим применение препарата в данной группе у лиц, не подвергающихся существенному риску, следует ограничить. • Необходимо обеспечить активный мониторинг генетических последовательностей вируса SARS-CoV-2 (например, полимеразы и спайк-белка), выделяемого из респираторных образцов пациентов, получающих лечение, в том числе лиц, находящихся в группе высокого риска (иммунодефицитные состояния). • Фармаконадзор: применение молнупиравира должно сопровождаться активной реализацией действенной программы фармаконадзора. 6.6.1. Механизм действия Молнупиравир является противовирусным средством для приема внутрь, которое было разработано как средство для лечения гриппа, однако не было одобрено. В лабораторных исследованиях показана высокая, сопоставимая с ремдесивиром активность данного лекарственного средства в отношении ингибирования репликации вируса SARS-CoV-2, и на раннем этапе разработки оно было перепрофилировано как противовирусное средство против вируса SARS-CoV-2 (47)(48). Молнупиравир является пролекарством для приема внутрь, которое метаболизируется в ß-D-N4-гидроксицитидин (NHC). Является нуклеозидным препаратом, механизм действия которого включает летальный мутагенез вируса. Данный механизм отличается от механизма терминации цепи, который присущ другим противовирусным средствам из группы нуклеозидных аналогов (например, ремдесивир и средства, используемые для лечения ВИЧ или гепатита С) (49). РНК-зависимая РНК-полимераза вируса SARS-CoV-2 встраивает NHC вместо нуклеотидов Ц или У в ходе копирования с матрицы геномной или субгеномной РНК. Синтезированные РНК, которые содержат NHC, используются в качестве матриц для дальнейшего синтеза последующих РНК, которые, как полагают, не могут приводить к образованию функциональных вирусов в связи с предполагаемым наличием мутаций (49)(50). В отличие от ремдесивира, который вводят внутривенно один раз в день, молнупиравир принимают внутрь два раза в сутки. После приема молнупиравира (800 мг) максимальная концентрация активного метаболита в плазме крови у здоровых добровольцев составляет 3600 нг/мл (51). Данный показатель выше, чем для ремдесивира (2200 нг/мл) (52). Вместе с тем в клеточных линиях человека период полувыведения активного метаболита молнупиравира из клеток менее продолжителен (3 ч.) по сравнению с выведением активного метаболита ремдесивира (35 ч.) (51). На модели переднеазиатских хомяков, зараженных вирусом SARS-CoV-2, показана эффективность высоких доз молнупиравира (250 мг/кг два раза в сутки); вместе с тем данные о фармакокинетике в плазме для сравнения с аналогичными показателями у человека предоставлены не были (53). Кроме того, данные о противовирусной активности в более низких дозах были представлены в исследовании на модели хорьков, зараженных вирусом SARS-CoV-2 (54). На модели зараженных переднеазиатских хомяков было показано, что эффективность комбинированного назначения молнупиравира и фавипиравира выше, чем при назначении каждого из препаратов в отдельности (55). 50 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Показано сохранение активности молнупиравира в отношении вариантов вируса «альфа» и «бета» в условиях in vivo (56), а также в отношении вариантов «дельта» и «омикрон» – в лабораторном эксперименте (57)(58). В настоящее время не имеется данных в пользу активности в отношении вариантов вируса «дельта» или «омикрон» в условиях in vitro, и, хотя, вероятно, на молекулярном уровне отсутствуют факторы снижения эффективности препарата, сохраняется неопределенность в отношении того, может ли более высокая скорость репликации или передачи вируса влиять на эффективность препарата. Возникновение устойчивости. Возникновение устойчивости к препаратам, используемым для лечения других вирусных инфекций, различается; в одних случаях она возникает достаточно быстро, тогда как в других – по прошествии более продолжительного времени. Как правило, считается, что барьер резистентности определенного вируса к определенному препарату тем выше, чем больше количество необходимых для этого мутаций. В настоящее время накоплено недостаточно данных для определения барьера резистентности вируса SARS-CoV-2 к молнупиравиру. Принимая во внимание опыт использования других нуклеозидных противовирусных препаратов (у некоторых барьер резистентности высок, тогда как у других он низок), молнупиравир создаст давление естественного отбора для возникновения резистентных мутаций на уровне индивидуумов с потенциалом распространения на уровне популяции. Таким образом, необходимы клинические и доклинические данные по молнупиравиру, которые в настоящее время отсутствуют. Возникновение резистентности обусловлено присущей вирусу вариабельностью генетических последовательностей, которая возникает спонтанно по мере репликации вируса. Если случайные вариации обусловливают повышение выживаемости в присутствии лекарственного средства, они закрепляются в отборе, то есть имеет место давление естественного отбора. В отдельных случаях приспособляемость вируса страдает, и впоследствии может происходить закрепление вторичных мутаций для восстановления приспособляемости. В основном неопределенность связана с темпами возникновения резистентности, нежели с возможностью ее появления. Кроме того, более высокий риск возникновения резистентности может наблюдаться у пациентов с иммуносупрессией ввиду более длительного периода продолжающейся репликации в данной группе. Кроме того, более высокий риск возникновения резистентности может наблюдаться у пациентов, неудовлетворительно соблюдающих предписанный режим, на фоне чего вирус подвергается воздействию лекарственного средства в недостаточной концентрации. Темпы появления резистентности будут ниже в случае назначения комбинации препаратов, так как для возникновения резистентности к комплексу препаратов необходимо большее количество мутаций, чем для резистентности к одному препарату. Необходимо заметить, что в исследованиях на животных также показана более высокая эффективность комбинаций препаратов. Наличие резистентности создает для пациентов риск слабой результативности использования лекарственного средства в связи с уменьшением эффективности. При дальнейшей передаче резистентности существует риск неэффективности лекарственного средства на уровне популяции, и последующие усилия по комбинированию препарата могут оказаться безрезультатными ввиду фактической «функциональной монотерапии» вторым средством из комбинации. В отсутствие необходимых данных оценка генетического барьера резистентности невозможна. Появление новых вариантов вируса. Выдвинуто предположение о том, что случайные мутации, возникающие в связи с механизмом действия молнупиравира, могут привести к повышению разнообразия вирусных генетических последовательностей и способствовать более быстрому появлению новых вариантов вируса (59). В отличие от соображений, относящихся к резистентности, концептуальной основы давления естественного отбора, создаваемого молнупиравиром и содействующего возникновению новых вариантов вируса, не имеется. Принимая во внимание, что молнупиравир встраивается в геноме на место двух нуклеотидных оснований из четырех, вариации генетических последовательностей будут ниже, чем при встраивании вместо любого нуклеотида. В настоящее время не имеется фактических данных, которые бы непосредственно подтверждали или опровергали гипотезу о вариантах вируса, в связи с чем количественная оценка данного риска невозможна. Признано, что темпы возникновения резистентности и риск дополнительного появления новых вариантов вируса на почве разнообразия вирусного генома выше при условии выполнения вмешательства для большого количества пациентов. Доклиническая безопасность Группа по разработке руководящих принципов изучила общедоступные данные о доклинической безопасности молнупиравира на основании документов заседания FDA, посвященного разрешению на использование молнупиравира в чрезвычайной ситуации (30 ноября 2021 г.) (60). Были затронуты следующие проблемы в области безопасности. • Данные о генетической токсичности свидетельствуют в пользу мутагенного действия молнупиравира в условиях in vitro, однако признаков мутагенности на модели животных выявлено не было. Группа по разработке руководящих принципов признала неполноту имеющихся данных и пришла к выводу о том, что на основании имеющейся информации канцерогенные свойства молнупиравира у человека не могут быть подтверждены или опровергнуты. • Утолщение ростковой пластинки, сопровождающееся снижением темпа образования костной ткани, наблюдалось у быстрорастущих крыс, однако не было выявлено у мышей, крыс или собак. В этой связи группа пришла к выводу о том, что молнупиравир не должен назначаться в педиатрической практике. • Важно заметить, что NHC в низкой концентрации (0,09% дозы, полученной матерью) обнаруживались в организме 10-дневных крысят, что указывает на выведение NHC с грудным молоком. Группа по разработке руководящих принципов пришла к выводу о том, молнупиравир не должен назначаться кормящим женщинам. • В ходе оценки онтогенетической и репродуктивной токсичности было выявлено снижения массы тела у крыс и кроликов, кроме того, на фоне поступления в организм высоких доз у крыс отмечены летальное воздействие на эмбрион и плод, а также тератогенные эффекты. Соответственно, молнупиравир не следует назначать в период беременности. • Отмечено отсутствие сведений, касающихся сперматогенеза, тогда как мутагенное действие может в значительной степени нарушать данную функцию во взрослом мужском организме. Не имеется данных для количественной оценки отрицательного воздействия препарата на эмбрион/плод, зачатый от мужчин, получающих или недавно закончивших прием молнупиравира. 51 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.7. Ингибиторы янус-киназ (опубликовано 14 января 2022 г.) Справочная информация Рекомендации по применению ингибиторов янус-киназ (JAK), в частности барицитиниба, руксолитиниба и тофацитиниба, для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 были опубликованы 14 января 2022 г. в восьмой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Они вышли в свет после опубликования трех РКИ по барицитинибу, двух РКИ по руксолитинибу и одного РКИ по тофацитинибу в соответствии с ОДСМА по лекарственной терапии (1). В одиннадцатую версию рекомендаций (данный документ) не было внесено изменений, касающихся ингибиторов JAK; вместе с тем авторы ознакомились с недавно опубликованными материалами исследования RECOVERY, которые содержат сведения в пользу ранее вынесенной рекомендации, и в настоящее время ведется анализ. Барицитиниб для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Дополнительные соображения содержатся в практическом резюме. Кроме того, полезная информация изложена в информационном бюллетене Управления по контролю за пищевыми продуктами и лекарствами США для поставщиков медицинских услуг, который был подготовлен на основе разрешения на использование барицитиниба в чрезвычайной ситуации (61). Ниже кратко обобщены основные положения. Пути введения, дозировка и продолжительность применения • Рекомендуемая доза составляет 4 мг в день внутрь для взрослых с рСКФ ≥ 60 мл/мин/1,73 м2. • Лечение продолжают до истечения 14 дней от начала приема препарата или до выписки из стационара в зависимости от того, какое событие наступит раньше. Оптимальная продолжительность лечения неизвестна, и предложенный срок отражает практику испытаний, на основе которых получены сведения о терапевтических эффектах барицитиниба. Корректировка режима дозирования • Пациенты с лейкопенией, недостаточностью функции почек или печени (примечание: данные параметры необходимо контролировать во время лечения). • Пациенты, принимающие мощные ингибиторы транспортеров органических анионов третьего типа (ОАТ3) (например, пробенецид): имеются лекарственные взаимодействия, требующие снижения дозы. Временные рамки. Терапию барицитинибом (так же, как и блокаторами рецепторов к IL-6) необходимо начинать одновременно с использованием системных кортикостероидов; конкретное время в течение госпитализации или конкретный период заболевания для начала терапии не определены. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред У пациентов с тяжелым или крайне тяжелым течением заболевания прием барицитиниба предположительно снижает смертность и продолжительность искусственной вентиляции легких, а также сокращает продолжительность госпитализации. По-видимому, серьезные неблагоприятные проявления на фоне применения препарата невелики или отсутствуют. Настоятельная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием барицитиниба (настоятельная рекомендация в пользу применения). • Наряду с барицитинибом пациенты с тяжелой и крайне тяжелой формой COVID-19 должны получать лечение кортикостероидами (см. раздел 6.15). • Ранее применение блокаторов рецепторов к IL-6 (тоцилизумаб и сарилумаб) рекомендовалось для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 (см. раздел 6.11). Блокаторы рецепторов к IL-6 не следует комбинировать с барицитинибом, и данные препараты необходимо рассматривать как взаимоисключающие. Выбор в пользу барицитиниба или блокатора рецепторов к IL-6 определяется доступностью соответствующего препарата, а также клиническими и другими обстоятельствами (см. раздел «Обоснование»). 52 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Анализ в подгруппах проводился для класса ингибиторов JAK в целом (не для отдельных препаратов) и не выявил признаков влияния на относительный риск в подгруппах пациентов молодого возраста (<70 лет) по сравнению с пожилыми пациентами; в подгруппах лиц с крайне тяжелым и тяжелым течением COVID-19; в подгруппах лиц, которые получали и не получали кортикостероиды в исходный момент времени; а также в подгруппах лиц, которые получали и не получали ремдесивир в исходный момент времени. Убедительность фактических данных Убедительность фактических данных была оценена следующим образом: средняя в отношении снижения смертности (оценка понижена с изначально высокой ввиду проведения масштабного исследования, результаты которого могут изменить оценку эффекта и косвенного характера данных в связи с вероятно недостаточной для регистрации всех важных событий продолжительностью периода катамнестического наблюдения около 28 дней); высокая в отношении сокращения продолжительности госпитализации; умеренная в отношении сокращения продолжительности искусственной вентиляции легких и в отношении незначительных или отсутствующих серьезных неблагоприятных проявлений (обе оценки понижены в связи с существенной неоднозначностью трактовки данных); низкая в отношении потребности в искусственной вентиляции легких (оценка снижена в связи с существенной неоднозначностью трактовки данных). Группа по разработке руководящих принципов отметила, в частности, что риск серьезных инфекций (бактериальных и грибковых) может значительно различаться в разных частях мира в зависимости от фоновой распространенности инфекций (таких как туберкулез). Данный факт может не иметь существенной важности, принимая во внимание малую продолжительность курса барицитиниба для лечения COVID-19, вместе с тем, ввиду ограниченной географической распространенности рассмотренных испытаний и коротких периодов наблюдения, объем накопленных фактических данных мал. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7), группа по разработке руководящих принципов пришла к выводу о том, что почти все надлежащим образом информированные пациенты с тяжелой или крайне тяжелой формой COVID-19 будут склонны получить барицитиниб ввиду вероятного снижения смертности и наличия данных средней степени убедительности в отношении незначительного или нулевого увеличения количества серьезных неблагоприятных проявлений. Группа пришла к выводу о том, что положительный эффект барицитиниба, связанный со снижением смертности, будет иметь решающее значение для пациентов, тогда как данные средней степени убедительности о незначительном или нулевом увеличении количества серьезных неблагоприятных проявлений расценены группой как дополнительный важный фактор. Группа по разработке руководящих принципов предположила, что различия ценностных ориентиров и предпочтений разных пациентов в отношении данного вмешательства будут незначительными. Ресурсная оснащенность и другие аспекты Последствия для ресурсной оснащенности, обеспечения равноправия и соблюдения прав человека Стоимость барицитиниба по сравнению с некоторыми другими рассматриваемыми средствами лечения COVID-19 высока. В этой рекомендации не принята во внимание экономическая эффективность. Доступ к данным препаратам во многих странах мира затруднен, и в отсутствие согласованных усилий данное положение дел, вероятно, сохранится, особенно в слабо обеспеченных ресурсами районах. Таким образом, эта настоятельная рекомендация может привести к усугублению неравенства в области здравоохранения. С другой стороны, принимая во внимание доказанные преимущества для пациентов, она должна обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этим средствам лечения. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Семнадцатого декабря 2021 г. ВОЗ опубликовала Седьмое приглашение для производителей лекарственных средств для лечения COVID-19 к подаче предварительных заявок на участие в оценке продукции, в том числе сотровимаба, в Департамент преквалификации ВОЗ. В период дефицита лекарственных средств может быть необходима приоритизация назначения барицитиниба в рамках клинической сортировки (6), например для пациентов, затронутых наивысшим риском смертности в исходный момент времени (например, лица с крайне тяжелым течением инфекции по сравнению с лицами с тяжелым течением), для которых абсолютная польза данного лечения является наибольшей. Другие предложения, касающиеся приоритизации, однако непосредственно не обоснованные фактическими данными, включают закрепление приоритета за пациентами с активно ухудшающейся динамикой заболевания и отказ от терапии барицитинибом лиц с установленной полиорганной недостаточностью (для которых преимущества, по-видимому, будут ниже). Приемлемость и практическая осуществимость Так как барицитиниб принимают один раз в сутки, очевидно, данное средство лечения может рассматриваться пациентами как удобное. Для приема барицитиниба пациентами, которые не имеют возможности проглатывать таблетки, допускается измельчение препарата с последующим растворением в воде и введением через назогастральный зонд (см. раздел «Практические сведения»). 53 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Обоснование При вынесении на основании фактических данных настоятельной рекомендации использовать барицитиниб у пациентов с тяжелой или крайне тяжелой формой COVID-19 группа подчеркнула присущие данному препарату преимущества в отношении показателя выживаемости и снижения продолжительности госпитализации, а также легкость введения и наличие незначительных или нулевых побочных эффектов. Группа признала вероятность того, что ряд серьезных побочных явлений, таких как грибковые инфекции, мог быть не учтен надлежащим образом в связи с относительно коротким периодом наблюдения в рассмотренных испытаниях. Ввиду различия механизмов действия, группа рассматривала барицитиниб отдельно от ингибиторов JAK (как указано ниже). К числу важных соображений относятся аспекты, связанные со стоимостью и обеспечению доступности, и группа признает, что данная рекомендация может усугубить неравенство в вопросах здоровья. Данная настоятельная рекомендация создаст стимул для решения указанных проблем и обеспечения доступности в различных регионах и странах. Группа предположила, что значимых различий ценностных ориентиров и предпочтений пациентов выявлено не будет, а другие ситуационные факторы не повлияют на рекомендацию (см. раздел, посвященный фактическим сведениям, лежащим в основе данного решения). Новые фактические данные При вынесении настоятельной рекомендации в пользу лечения барицитинибом группа по разработке руководящих принципов тщательно проанализировала роль еще не опубликованного крупного исследования (RECOVERY), в котором пациентов рандомизировали в группы с назначением и без назначения барицитиниба. К недостаточно изученным вопросам данного исследования относятся доля пациентов, которые также получали блокаторы рецепторов к IL-6 (см. ниже), и сроки появления доступных сведений. По мнению группы по разработке руководящих принципов, преимущества барицитиниба, подтвержденные фактическими данными с уровнем убедительности от средней до высокой, достаточны для непосредственного вынесения настоятельной рекомендации в пользу применения препарата с последующими обновлениями вариативных рекомендаций по мере необходимости после опубликования данных исследования RECOVERY. В настоящее время исследование RECOVERY опубликовано, и его данные подтверждают пользу применения барицитиниба у пациентов с тяжелым и крайне тяжелым течением COVID-19. После обновления ОДСМА перед выходом следующей версии рекомендаций группа по разработке руководящих принципов проведет полную оценку обновленных фактических сведений по барицитинибу. Значение блокаторов рецепторов к IL-6 и барицитиниба Ранее группой была вынесена настоятельная рекомендация применять блокаторы рецепторов к IL-6 (тоцилизумаб и сарилумаб) у пациентов с тяжелым или крайне тяжелым течением COVID-19. Группа тщательно проанализировала вопрос о достаточности имеющихся данных для применения барицитиниба в качестве альтернативы блокаторам рецепторов к IL-6 или в дополнение к блокаторам рецепторов к IL-6. Комбинирование данных препаратов может привести к неприемлемому увеличению риска вредных последствий, в том числе вторичных бактериальных и грибковых инфекций. В отсутствие сведений о дополнительной пользе группа рекомендует клиницистам не применять эти препараты в комбинации. Кроме того, остается нерешенным вопрос выбора между блокаторами рецепторов к IL-6 и барицитинибом (см раздел «Данные по итогам исследования»). Прямого сравнения этих препаратов не выполнялось, в связи с чем оптимальным доказательством их относительных эффектов являются косвенные сравнения, полученные в ОДСМА, на основе которого подготовлены настоящие руководящие принципы. По сравнению с блокаторами рецепторов к IL-6 на фоне приема барицитиниба наблюдается снижение показателя смертности (низкая степень убедительности) и продолжительности искусственной вентиляции легких (низкая степень убедительности). Различия по критерию потребности в искусственной вентиляции легких при приеме какого-либо из этих двух средств минимальны или отсутствуют (низкая степень убедительности), и, по-видимому, минимальны или отсутствуют различия по критерию неблагоприятных побочных явлений (средняя степень убедительности) (см. сводную таблицу результатов наблюдений в разделе «Данные по итогам исследования»). По мнению группы, данные низкой степени убедительности недостаточны для вынесения рекомендации в пользу преимущественного применения барицитиниба по сравнению с блокаторами рецепторов к IL-6 на основании влияния данных средств на важные для пациентов преимущества и риски вредных последствий. Таким образом, клиницисты должны руководствоваться иными соображениями в случае доступности препаратов обеих групп. К числу этих соображений могут относиться опыт и удобство применения этих препаратов; политика конкретного лечебного учреждения; пути введения препаратов (барицитиниб принимают внутрь; блокаторы рецепторов к IL-6 вводят внутривенно); и соображения стоимости. Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Кроме того, остается неопределенность в отношении использования барицитиниба у беременных и кормящих женщин. Решение касательно использования данного лекарственного средства должно приниматься беременной женщиной и ее лечащим врачом с учетом соотношения потенциальной пользы и возможного риска для матери и плода (см. вкладки «Данные по итогам исследования» и «Практические сведения»). 54 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: Пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: барицитиниб Сравнение: стандарт оказания помощи Резюме Резюме фактических данных В основу ОДСМА по барицитинибу были положены данные трех РКИ с участием 2659 пациентов с различной тяжестью заболевания (62)(63)(64). Все эти РКИ были зарегистрированными, два из них были опубликованы в рецензируемых научных журналах (63)(64); одно исследование было доступно в форме предварительной публикации (62). Во все три РКИ проводился набор стационарных пациентов. Ни в одном из включенных исследований не участвовали дети или беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения барицитиниба по сравнению со стандартом оказания помощи для пациентов с тяжелым и крайне тяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных на основании ОДСМА (1). Оценка риска в исходный момент времени Для оценки важного показателя смертности в группе пациентов с тяжелым и крайне тяжелым течением заболевания был взят оценочный показатель исходного риска наступления летального исхода, равный 13% (130 случаев на 1000 пациентов). Как и в отношении других соответствующих рекомендаций, представленных в данном документе, величина исходного риска смертности заимствована из исследования SOLIDARITY для пациентов с тяжелой и крайне тяжелой формами COVID-19 с внесением поправки на лечебный эффект применения кортикостероидов. При оценке исходного риска наступления других исходов группа по разработке руководящих принципов использовала медианное значение соответствующего показателя в контрольной группе РКИ, данные которых включались в анализ (см. раздел 7). Анализ в подгруппах Четыре аналитических исследования в заранее определенных подгруппах были проведены не для отдельных препаратов, а для класса ингибиторов JAK в целом. 1. Возраст: взрослые пациенты молодого возраста (моложе 70 лет) по сравнению с лицами старшего возраста (70 лет и старше). 2. Тяжесть течения заболевания (на момент начала лечения): нетяжелое по сравнению с тяжелым и крайне тяжелым течением. 3. Одновременное назначение кортикостероидов в исходный момент времени. 4. Одновременное назначение ремдесивира в исходный момент времени. Данных в пользу взаимосвязи принадлежности к подгруппе с относительным риском важнейших исходов для всех заранее указанных модификаторов эффекта выявлено не было. Исход Период времени Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Барицитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,62 (95% ДИ: 0,44–0,85) На основании данных по 2659 пациентам в 3 исследованиях (рандомизированные контролируемые) 130 на 1000 85 на 1000 Средняя В связи с продолжающимся набором в крупное РКИ Предположительно, применение барицитиниба приводит к снижению показателя смертности. Разница: сокращение на 45 случаев на 1000 (95% ДИ: сокращение на 68 случаев – сокращение на 17 случаев) Искусственная вентиляция легких Отношение шансов: 0,8 (95% ДИ: 0,52–1,19) На основании данных по 2434 пациентам в 2 исследованиях (рандомизированные контролируемые) 116 на 1000 95 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных1 Вероятно, применение барицитиниба приводит к снижению потребности в искусственной вентиляции легких Разница: сокращение на 21 случай на 1000 (95% ДИ: сокращение на 52 случая – увеличение на 19 случаев) 55 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исход Период времени Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Барицитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Нежелательные явления, приводящие к отмене препарата На основании данных по 1611 пациентам в 2 исследованиях (рандомизированные контролируемые) 0 на 1000 5 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных2 Предположительно, применение барицитиниба приводит к незначительному или нулевому повышению частоты нежелательных эффектов. Разница: увеличение на 5 случаев на 1000 (95% ДИ увеличение на 0 случаев – увеличение на 28 случаев) Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 2652 участникам в 3 исследованиях (рандомизированные контролируемые) 12,8 дня (медианное значение) 11,4 дня (среднее значение) Высокая Барицитиниб приводит к сокращению продолжительности госпитализации. Разница: СО: сокращение на 1,4 (95% ДИ: сокращение на 2,4 случая – сокращение на 0,4 случая) Продолжительность искусственной вентиляции легких Предпочтителен более низкий уровень На основании данных по: 328 участникам в 2 исследованиях (рандомизированные контролируемые) 14,7 дня (медианное значение) 11,5 дня (среднее значение) Средняя Ввиду существенной неоднозначности трактовки данных3 Предположительно, применение барицитиниба приводит к сокращению продолжительности искусственной вентиляции легких. Разница: СО: сокращение на 3,2 (95% ДИ: сокращение на 5,9 случая – сокращение на 0,5 случая) Время до клинического улучшения состояния Меньший показатель предпочтителен На основании данных по: 2558 участникам в 2 исследованиях (рандомизированные контролируемые) 9,9 дня (медианное значение) 8,9 дня (среднее значение) Низкая Ввиду крайней неоднозначности трактовки данных4 Прием барицитиниба вероятно способствует сокращению период времени до клинического улучшения состояния Разница: СР на 1 меньше (95% ДИ: меньше на 2,9 дня – больше на 1,1 дня) 1. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного сокращения, так и существенного увеличения сроков искусственной вентиляции легких. 2. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область существенного увеличения нежелательных эффектов. 3. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область несущественных различий. 4. Неоднозначность трактовки данных: крайняя. Доверительный интервал охватывает как область существенного вреда, так и существенных преимуществ (для минимально значимых различий используется пороговое значение 1 день). 56 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: барицитиниб Сравнение: блокаторы рецепторов к интерлейкину-6 Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Блокаторы рецепторов к IL-6 Вмешательство барицитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,77 (95% ДИ: 0,53–1,1) На основании данных по 2659 пациентам в 3 исследованиях (рандомизированные контролируемые) 118 на 1000 96 на 1000 Низкая Ввиду существенной неоднозначности трактовки данных и продолжающегося набора в крупное РКИ1 Вероятно, применение барицитиниба приводит к снижению показателя смертности. Разница: сокращение на 22 случая на 1000 (95% ДИ: сокращение на 52 случая – увеличение на 9 случаев) Искусственная вентиляция легких Отношение шансов: 1,01 (95% ДИ: 0,61–1,6) На основании данных по 2434 пациентам в 2 исследованиях (рандомизированные контролируемые) 94 на 1000 96 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных2 Вероятно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует. Разница: увеличение на 2 случая на 1000 (95% ДИ: сокращение на 38 случаев – увеличение на 44 случая) Нежелательные явления, приводящие к отмене препарата На основании данных по 2309 пациентам в 4 исследованиях (рандомизированные контролируемые) 0 на 1000 1 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Предположительно, различия по критерию нежелательных явлений, приводящих к отмене, минимальны или отсутствуют Разница: увеличение на 1 случай на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 15 случаев) Продолжительность госпитализации Предпочтителен более низкий уровень На основании данных по: 2652 участникам в 3 исследованиях (рандомизированные контролируемые) 8,1 дня (медианное значение) 11,2 дня (среднее значение) Крайне низкая В связи с высокой вероятностью систематической ошибки, существенным неединообразием данных и крайней неоднозначностью их трактовки4 Влияние на сокращение сроков госпитализации остается крайне неопределенным. Разница: СО: увеличение на 3,1 (95% ДИ: сокращение на 3,8 случая – увеличение на 9,9 случая) Продолжительность искусственной вентиляции легких Предпочтителен более низкий уровень На основании данных по: 328 участникам в 2 исследованиях (рандомизированные контролируемые) 13,8 дня (медианное значение) 11,6 дня (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки5 Вероятно, применение барицитиниба способствует сокращению продолжительности искусственной вентиляции легких. Разница: СО: сокращение на 2,2 (95% ДИ: сокращение на 5,3 случая – сокращение на 0,7 случая) Время до клинического улучшения состояния Предпочтителен более низкий уровень На основании данных по: 2558 участникам в 2 исследованиях (рандомизированные контролируемые) 8,4 дня (медианное значение) 8,9 дня (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки6 Существенное влияние на сроки до клинического улучшения состояния может отсутствовать. Разница: СО: увеличение на 0,5 (95% ДИ: сокращение на 2,3 случая – увеличение на 3,2 случая) 57 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область несущественных различий. 2. Риск систематической ошибки: серьезный риск отсутствует. Большая часть данных о блокаторах рецепторов к интерлейкину-6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. 3. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область незначительного, однако вместе с тем важного вреда. 4. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину- 6 накоплена в исследованиях, в которых имело место раскрытие данных. Неединообразие: существенное. Результаты исследований, посвященных блокаторам рецепторов к интерлейкину-6, противоречивы: прием ряда препаратов приводил к повышению продолжительности госпитализации, тогда как прием других – к сокращению. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. 5. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину- 6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область несущественных различий. 6. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину- 6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: существенная. Доверительный интервал охватывает как область существенного вреда, так и существенных преимуществ (для минимально значимых различий используется пороговое значение 1 день). Применение руксолитиниба и тофацитиниба для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Пути введения, дозировка и продолжительность применения. В отсутствие иных сведений для подготовки рекомендаций по применению данных средств авторы опирались на таблицу важнейших характеристик (руксолитиниба и тофацитиниба). Временные рамки. Терапию руксолитинибом или тофацитинибом (так же, как и блокаторами рецепторов к IL-6) необходимо начинать одновременно с системными кортикостероидами; конкретное время в течение госпитализации или конкретный период заболевания для начала терапии не определены. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Влияние применения руксолитиниба или тофацитиниба на потребность в искусственной вентиляции легких или продолжительность госпитализации остается неясным. На фоне приема тофацитиниба могут наблюдаться нежелательные явления, приводящие к отмене препарата. Анализ в подгруппах проводился для класса ингибиторов JAK в целом (не для отдельных препаратов) и не выявил признаков влияния на относительный риск в подгруппах пациентов молодого возраста (< 70 лет) по сравнению с пациентами старшего возраста; в подгруппах лиц, которые получали и не получали кортикостероиды; в подгруппах лиц с тяжелым и крайне тяжелым течением COVID-19; а также в подгруппах лиц, которые получали и не получали ремдесивир. Убедительность фактических данных Ввиду существенной неоднозначности трактовки данных, обусловленной малой численностью когорт (руксолитиниб: два РКИ, 475 пациентов; тофацитиниб: одно РКИ, 289 пациентов) с небольшим количеством событий, а также ввиду крайне косвенного характера данных (относящихся к РКИ руксолитиниба, в которых большинство пациентов не получали кортикостероиды), степень убедительности фактических данных оценена как низкая или крайне низкая для всех приоритетных результатов для обоих препаратов. Условная рекомендация не применять Новые сведения Рекомендуется не применять руксолитиниб и тофацитиниб (условная рекомендация не применять). • Клиницистам следует рассматривать возможность использования данных препаратов только в том случае, если ни барицитиниб, ни блокаторы рецепторов к IL-6 (тоцилизумаб или сарилумаб) недоступны. • Группа по разработке руководящих принципов подчеркнула необходимость сбора большего объема фактических данных для более убедительного обоснования рекомендаций. 58 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Ценностные ориентиры и предпочтения Опираясь на согласованный перечень ценностных ориентиров и предпочтений (см. раздел 7), группа по разработке руководящих принципов предположила, что, с учетом низкой или крайне низкой степени убедительности данных о смертности и других приоритетных преимуществах, а также с учетом сохраняющейся вероятности серьезных побочных явлений, большинство надлежащим образом информированных пациентов воздержатся от применения руксолитиниба или тофацитиниба. Вместе с тем группа по разработке руководящих принципов предположила, что ввиду возможного наличия положительного эффекта, а также ввиду вероятного наличия эффекта ингибиторов JAK как класса препаратов (в частности, наблюдения, относящиеся к барицитинибу, косвенно доказывают преимущества других ингибиторов JAK), меньшая часть надлежащим образом информированных пациентов предпочтет получить тот или иной препарат в условиях, в которых недоступны ни барицитиниб, ни блокаторы рецепторов к IL-6 (тоцилизумаб или сарилумаб). Ресурсная оснащенность и другие аспекты Последствия для ресурсной оснащенности, обеспечения равноправия и соблюдения прав человека Группа по разработке руководящих принципов отметила, что, принимая во внимание рекомендацию не использовать руксолитиниб или тофацитиниб, необходимо сконцентрировать усилия по обеспечению доступа к лекарственным средствам на препаратах, рекомендуемых в настоящее время. Приемлемость и практическая осуществимость Так как руксолитиниб и тофацитиниб принимают внутрь два раза в сутки, данное средство должно быть удобным для госпитализированных пациентов с тяжелым и крайне тяжелым течением COVID-19. В случае, если пациент не имеет возможности проглатывать препарат в таблетированной форме, допускается измельчение и растворение барицитиниба в воде для последующего употребления внутрь или введения через назогастральный зонд (см. раздел «Практические сведения»). Обоснование При вынесении на основании фактических данных условной рекомендации не использовать руксолитиниб или тофацитиниб у пациентов с тяжелым и крайне тяжелым течением COVID-19, группа по разработке руководящих принципов подчеркнула, что степень убедительности фактических данных в отношении смертности, продолжительности искусственной вентиляции легких и возможного повышения частоты серьезных неблагоприятных проявлений находится в диапазоне от низкой до крайне низкой (особенно для тофацитиниба). Группа по разработке руководящих принципов подчеркнула важность сбора большего объема фактических данных в рамках исследований для более убедительного обоснования рекомендаций; применение данного подхода ожидается в ходе продолжающихся исследований упомянутых ингибиторов JAK. Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Кроме того, остается неопределенность в отношении использования руксолитиниба или тофацитиниба у беременных и кормящих женщин. Клиническая проблема/вопрос PICO Популяция: Пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: руксолитиниб Сравнение: стандарт оказания помощи Резюме Резюме фактических данных В основу ОДСМА по руксолитинибу были положены два РКИ с участием 475 пациентов из подгрупп нетяжелого, тяжелого и крайне тяжелого течения заболевания (65)(66). Оба РКИ были зарегистрированы, данные одного из них были опубликованы в рецензируемом журнале, тогда как данные о другом содержались только в регистрационной документации. Во все три РКИ проводился набор стационарных пациентов. Ни в одном из включенных исследований не участвовали дети или беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения руксолитиниба по сравнению со стандартом оказания помощи для пациентов с тяжелым и крайне тяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах Группа по разработке руководящих принципов предварительно определила несколько актуальных аналитических исследований в подгруппах для всех ингибиторов JAK, представляющих интерес; значимого относительного эффекта в подгруппах выявлено не было. Подробные сведения изложены в резюме, которое сопровождает рекомендацию в отношении использования барицитиниба. 59 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство руксолитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,87 (95% ДИ: 0,27–2,85) На основании данных по 472 пациентам в 2 исследованиях (рандомизированные контролируемые) 130 на 1000 115 на 1000 Очень низкая Ввиду крайне косвенного характера данных и крайней неоднозначности трактовки1 Влияние приема руксолитиниба остается крайне неопределенным. Разница: сокращение на 15 случаев на 1000 (95% ДИ: сокращение на 91 случай – увеличение на 169 случаев) Искусственная вентиляция легких Отношение шансов: 0,87 (95% ДИ: 0,36–2,04) На основании данных по 472 пациентам в 2 исследованиях (рандомизированные контролируемые) 116 на 1000 108 на 1000 Очень низкая Ввиду крайне косвенного характера данных и крайней неоднозначности трактовки2 Влияние приема руксолитиниба остается крайне неопределенным. Разница: сокращение на 8 случаев на 1000 (95% ДИ: сокращение на 71 случай – увеличение на 94 случая) Нежелательные явления, приводящие к отмене препарата Данные по 484 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 0 на 1000 5 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных3 На фоне приема руксолитиниба может не наблюдаться значимого повышения частоты нежелательных явлений, приводящих к отмене препарата. Разница: увеличение на 2 случая на 1000 (95% ДИ увеличение на 0 случаев – увеличение на 15 случаев) Продолжительность госпитализации На основании данных по 484 пациентам в 1 исследовании (рандомизированные контролируемые) 12,8 дня (медианное значение) 11,4 дня (среднее значение) Очень низкая Ввиду крайне косвенного характера данных и крайней неоднозначности трактовки4 Влияние применения руксолитиниба на продолжительность госпитализации остается крайне неопределенным. Разница: СО: увеличение на 0,1 (95% ДИ: сокращение на 2,1 случая – увеличение на 2,4 случая) Продолжительность искусственной вентиляции легких Предпочтителен более низкий уровень На основании данных по: 3 участникам в 1 исследовании (рандомизированные контролируемые) 14,7 дня (медианное значение) Крайне низкая Недостаточный объем данных5 Влияние применения руксолитиниба на потребность в искусственной вентиляции легких не определено. Время до клинического улучшения состояния Предпочтителен более низкий уровень На основании данных по: 472 участникам в 2 исследованиях (рандомизированные контролируемые) 9,9 дня (медианное значение) 9,8 дня (среднее значение) Очень низкая Ввиду крайне косвенного характера данных и крайней неоднозначности трактовки6 Влияние применения руксолитиниба на время до клинического улучшения состояния остается крайне неопределенным. Разница: СО: сокращение на 0,1 (95% ДИ: сокращение на 2,5 случая – увеличение на 2,8 случая) 1. Косвенный характер данных: существенный. По-видимому, большинство пациентов не получали кортикостероиды в начальный момент времени. Одновременное применение кортикостероидов усиливает положительное действие блокаторов рецепторов интерлейкина-6. Интерлейкин-6 участвует в нисходящей передаче в янус-киназном пути. Таким образом, в случае применения стероидов у большинства пациентов был бы возможен более выраженный эффект руксолитиниба. Кроме того, в исследование руксолитиниба, по-видимому, было включено большое количество пациентов с нетяжелым течением заболевания. Положительный эффект ингибиторов янус-киназ может ограничиваться группой пациентов с крайне тяжелой или тяжелой формой заболевания. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. 60 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 2. Косвенный характер данных: существенный. По-видимому, большинство пациентов не получали кортикостероиды в начальный момент времени. Одновременное применение кортикостероидов усиливает положительное действие блокаторов рецепторов интерлейкина-6. Интерлейкин-6 участвует в нисходящей передаче в янус-киназном пути. Таким образом, в случае применения стероидов у большинства пациентов был бы возможен более выраженный эффект руксолитиниба. Кроме того, в исследование руксолитиниба, по-видимому, было включено большое количество пациентов с нетяжелым течением заболевания. Положительный эффект ингибиторов янус-киназ может ограничиваться группой пациентов с крайне тяжелой или тяжелой формой заболевания. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенного вреда, так и существенных преимуществ. 3. Неоднозначность трактовки данных: крайняя. Информация о данном конечном результате поступила только однократно из одного исследования с 424 участниками. 4. Косвенный характер данных: существенный. По-видимому, большинство пациентов не получали кортикостероиды в начальный момент времени. Одновременное применение кортикостероидов усиливает положительное действие блокаторов рецепторов интерлейкина-6. Интерлейкин-6 участвует в нисходящей передаче в янус-киназном пути. Таким образом, в случае применения стероидов у большинства пациентов был бы возможен более выраженный эффект руксолитиниба. Кроме того, в исследование руксолитиниба, по-видимому, было включено большое количество пациентов с нетяжелым течением заболевания. Положительный эффект ингибиторов янус-киназ может ограничиваться группой пациентов с крайне тяжелой или тяжелой формой заболевания. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. 5. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. 6. Косвенный характер данных: существенный. По-видимому, большинство пациентов не получали кортикостероиды в начальный момент времени. Одновременное применение кортикостероидов усиливает положительное действие блокаторов рецепторов интерлейкина-6. Интерлейкин-6 участвует в нисходящей передаче в янус-киназном пути. Таким образом, в случае применения стероидов у большинства пациентов был бы возможен более выраженный эффект руксолитиниба. Кроме того, в исследование руксолитиниба, по-видимому, было включено большое количество пациентов с нетяжелым течением заболевания. Положительный эффект ингибиторов янус-киназ может ограничиваться группой пациентов с крайне тяжелой или тяжелой формой заболевания. Неоднозначность трактовки данных: крайняя. Доверительный интервал охватывает как область существенного вреда, так и существенных преимуществ (для минимально значимых различий используется пороговое значение 1 день). Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: тофацитиниб Сравнение: стандарт оказания помощи Резюме Резюме фактических данных В основу ОДСМА по тофацитинибу были положены данные одного РКИ с участием 289 пациентов из подгрупп нетяжелого, тяжелого и крайне тяжелого течения заболевания (67). Исследование было зарегистрировано, информация о нем опубликована в рецензируемом журнале; из исследования исключены дети и беременные женщины. Характеристики данных РКИ показаны в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, указаны относительные и абсолютные эффекты применения тофацитиниба по сравнению со стандартом оказания помощи для пациентов с тяжелым и крайне тяжелым течением COVID-19 в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах Группа по разработке руководящих принципов предварительно определила несколько актуальных аналитических исследований в подгруппах для всех ингибиторов JAK, представляющих интерес; значимого относительного эффекта в подгруппах выявлено не было. Подробные сведения изложены в резюме, которое сопровождает рекомендацию в отношении использования барицитиниба. 61 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство тофацитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,47 (95% ДИ: 0,11–1,63) Данные по 289 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 130 на 1000 78 на 1000 Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных1 Влияние тофацитиниба не определено. Разница: сокращение на 52 случая на 1000 (95% ДИ: сокращение на 113 случаев – увеличение на 69 случаев) Искусственная вентиляция легких Отношение шансов: 0,5 (95% ДИ: 0,17–1,37) Данные по 289 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 116 на 1000 68 на 1000 Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных2 Влияние тофацитиниба не определено. Разница: сокращение на 48 случаев на 1000 (95% ДИ: сокращение на 94 случая – увеличение на 35 случаев) Нежелательные явления, приводящие к отмене препарата Данные по 284 пациентам, полученные в 1 исследовании (рандомизированные контролируемые) 0 на 1000 77 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных3 На фоне приема тофацитиниба могут наблюдаться нежелательные явления, приводящие к отмене препарата. Разница: увеличение на 77 случаев на 1000 (95% ДИ увеличение на 17 случаев – увеличение на 138 случаев) Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 289 участникам в 1 исследовании (рандомизированные контролируемые) 12,8 дня (медианное значение) 11,7 дня (среднее значение) Низкая Ввиду крайней неоднозначности трактовки данных4 Тофацитиниб может способствовать сокращению продолжительности госпитализации. Разница: СО: сокращение на 1,1 (95% ДИ: сокращение на 2,8 случая – увеличение на 0,6 случая) Продолжительность искусственной вентиляции легких 14,7 дня (медианное значение) Крайне низкая Нет данных Влияние применения тофацитиниба на продолжительность искусственной вентиляции легких не определено. Время до клинического улучшения состояния 9,9 дня (медианное значение) Крайне низкая Нет данных Влияние приема тофацитиниба на время до клинического улучшения состояния пациентов не определено. 1. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. Всего было зарегистрировано только 12 событий. 2. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. Всего было зарегистрировано только 18 событий. 3. Неоднозначность трактовки данных: крайняя. Крайне малое количество событий: всего 21 (16/142 в группе тофацитиниба и 5/142 в группе плацебо). 4. Неоднозначность трактовки данных: крайняя. Доверительные интервалы не накрывают области существенных различий. 62 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.7.1. Механизм действия Рецепторы цитокинов I и II типа являются семейством рецепторов, через которые опосредуется действие более 50 интерлейкинов, интерферонов, колониестимулирующих факторов и гормонов (68). Каскады внутриклеточного сигналинга, запускаемые данными рецепторами, опосредуются янус-киназами (JAK), небольшим семейством киназ, включающим JAK1, JAK2, JAK3 и тирозинкиназу 2 (TYK2). К цитокинам I типа относятся IL-2, IFN-γ, IL-12 и TNFb; к цитокинам II типа относятся IL-4, IL-5, IL-6, IL-10 и IL-13. Ингибиторы JAK – это класс лекарственных средств, ингибирующих внутриклеточный сигналинг посредством многообразных воздействий на цитокиновый сигнальный путь. Вследствие этого, они влияют на многие клеточные реакции, включая противовирусный ответ, экспрессию ангиотензинпревращающего фермента 2 (AПФ2), функционирование и дифференцировку Т-клеток и активацию макрофагов (68). Барицитиниб, руксолитиниб и тофацитиниб – три из по меньшей мере девяти ингибиторов JAK. Все эти три препарата зачастую считаются неспецифическими ингибиторами JAK, однако различия в специфичности и эффективности для разных JAK очевидны. Барицитиниб описан как ингибитор JAK1/JAK2, руксолитиниб – как ингибитор JAK1/JAK2 > TYK2, тофацитиниб – как ингибитор JAK3/JAK1 > JAK2/TYK2; кроме того, ранее также были описаны другие различия (68)(69)(70). Дозировка ингибиторов JAK в исследованиях, посвященных лечению COVID-19, была той же или выше, чем одобренная для других показаний, таких как ревматоидный артрит, миелофиброз и язвенный колит. Таким образом, убедительность наблюдений определяется ролью цитокинового сигналинга при COVID-19, и вопрос об удовлетворительности фармакокинетики при использовании препаратов в изученной дозировке для ингибирования белков-мишеней не актуален. Имеются существенные различия в одобренных дозах, режимах, фармакокинетических параметрах, противопоказаниях и показаниях этих препаратов при других нозологиях. В совокупности эти различия не позволяют вынести рекомендацию на уровне класса в целом на основе имеющихся данных. 63 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.8. Сотровимаб (опубликовано 14 января 2022 г.) Справочная информация Рекомендации по применению сотровимаба для лечения пациентов с нетяжелым течением COVID-19 были опубликованы 14 января 2022 г. в восьмой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Рекомендации были выпущены после опубликования результатов одного из РКИ, в котором изучалось нетяжелое течение заболевания, в рамках ОДСМА, посвященного терапии с использованием антител и клеток (2). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся сотровимаба, внесено не было. В настоящее время группа по разработке руководящих принципов проводит оценку того, в какой степени все более активно распространяющийся вариант вируса «омикрон» ВА.2 способствует снижению клинической эффективности сотровимаба, о чем на данном этапе свидетельствуют данные доклинических исследований в условиях in vitro (см. «Механизм действия»). Кроме того, группа подчеркивает, что для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации, имеется ряд альтернатив (см. раздел 6.1 и примечания под текстом рекомендаций). Для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации Практические сведения Пути введения, дозировка и продолжительность применения. Дополнительные соображения содержатся в практическом резюме. Ниже кратко обобщены основные положения. • Разрешенная дозировка сотровимаба: однократное внутривенное введение в дозе 500 мг в течение 30 минут в как можно более короткие сроки после получения положительного результата тестирования на вирус SARS-CoV-2 и в течение 10 дней от момента появления симптомов. • Сотровимаб доступен в виде концентрированного раствора, который необходимо развести перед введением. • Необходимо наблюдать за пациентами во время введения препарата, а также в течение не менее 1 часа после завершения инфузии. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред У пациентов с нетяжелым течением заболевания сотровимаб, вероятно, сокращает продолжительность госпитализации, практически не влияя на инфузионные реакции, при этом данных о времени до клинического улучшения не имеется. Вероятно, сотровимаб оказывает слабое или нулевое влияние на показатель смертности или потребность в искусственной вентиляции легких. В отсутствие обнародованных или предоставленных исследователями данных в подгруппах планируемый анализ в разбивке по подгруппам не мог быть выполнен. Условная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием сотровимаба (настоятельная рекомендация в пользу применения). • Информация для содействия выявлению пациентов, затронутых наивысшим риском госпитализации, содержится в разделе 6.1. • Доступен ряд вариантов лечения: см. инструмент содействия принятию решений, в котором представлены сведения о пользе и вреде применения комбинации нирматрелвира и ритонавира, молнупиравира, ремдесивира и моноклональных антител, в том числе сотровимаба и комбинации казиривимаба и имдевимаба. • Группа по разработке руководящих принципов пришла к выводу о том, что комбинация нирматрелвира и ритонавира, вероятно, является наилучшим вариантом лечения, так как данные средства, вероятно, обладают большей эффективностью в отношении профилактики госпитализации по сравнению с альтернативами, обладают меньшим количеством эффектов, вызывающих обеспокоенность, по сравнению с молнупиравиром и более удобны при приеме по сравнению с ремдесивиром или антителами, требующими внутривенного введения. • Вариант «омикрон» ВА.2 может приводить к значительному снижению клинической эффективности сотровимаба; в настоящее время группа по разработке руководящих принципов проводит анализ данной проблемы. • Пациенты с тяжелой или крайне тяжелой формой COVID-19: принимая во внимание имеющиеся данные, польза сотровимаба у серонегативных пациентов с тяжелой или крайне тяжелой формой COVID-19 (см. рекомендацию в отношении комбинации казиривимаба и имдевимаба в разделе 6.10) остается невыясненной. Иными словами, при рассмотрении возможности назначения сотровимаба в связи с недоступностью комбинации казиривимаба и имдевимаба, необходимо опираться на тщательный анализ клинической ситуации. 64 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Убедительность фактических данных В основу резюме фактических данных было положено одно РКИ с участием 1057 пациентов (COMET-ICE), включенное в ОДСМА (74). В данном исследовании содержатся сведения средней степени убедительности в пользу сокращения сроков госпитализации (ввиду существенной неоднозначности трактовки данных), высокой степени убедительности в пользу отсутствия инфузионных реакций, средней степени убедительности (ввиду крайне косвенного характера данных) в пользу отсутствия или малого различия по критерию смертности и низкой степени убедительности (ввиду крайне косвенного характера данных и неоднозначности трактовки) в пользу малых или нулевых различий по критерию искусственной вентиляции легких. Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных ввиду их косвенного характера, обусловленного главным образом ограниченной доступностью разработанного эмпирическим путем метода прогнозирования риска, позволяющего определять риск госпитализации у отдельных пациентов. Кроме того, эксперты группы сочли, что определенную роль в косвенном характере данных играет возможность появления новых вариантов вируса, против которых терапия доступными в настоящее время моноклональными антителами, вероятно, будет менее эффективна. При оценке степени точности данных группа приняла во внимание оценки абсолютного риска. Таким образом, для условий очень низкой частоты событий (например, очень низкий риск летального исхода в группе пациентов с нетяжелым течением заболевания) группа не снижала оценку в связи с неоднозначностью трактовки, несмотря на наличие относительных рисков с широкими доверительными интервалами. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы пришли к выводу о том, что почти все надлежащим образом информированные пациенты, чей риск госпитализации, как правило, является низким, будут склонны отказаться от применения сотровимаба, и только пациенты из группы высокого риска (например, невакцинированные лица, пожилые люди, лица с иммунодефицитными состояниями) предпочтут получить данное лечение. В связи с отсутствием научных данных в ходе предыдущего обследования (см. рекомендацию в отношении комбинации казиривимаба и имдевимаба), группа высказала мнение о том, что большинство пациентов с риском госпитализации более 10%, и, соответственно, снижением абсолютного риска примерно на 6%, предпочтут пройти лечение, в то время как большинство пациентов с риском ниже этого уровня будут склонны воздержаться от него. Эти пороговые значение также применялись в данном случае. Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Группа по разработке руководящих принципов отметила низкую вероятность того, что лечение сотровимабом будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Это положение еще раз подтверждает вынесенную рекомендацию, предписывающую назначать сотровимаб только пациентам с наивысшим риском госпитализации. К числу дополнительных трудностей относится необходимость внутривенного введения препарата пациентам, состояние которых обычно предполагает лечение на дому. Для обеспечения безопасного и эффективного использования сотровимаба могут быть необходимы услуги специализированных клиник. Таким образом, для того, чтобы рассматриваемое вмешательство получило широкое применение, системы здравоохранения должны будут решить перечисленные проблемы. Принимая во внимание стоимость и доступность сотровимаба, препятствия для обеспечения доступности в СНСД могут оказаться чрезвычайно серьезными. Например, доступ к услугам в первые пять дней от момента появления симптомов, а также доступ к вмешательствам зачастую бывает затруднен для лиц, находящихся в неблагоприятном социально-экономическом положении. Таким образом, рекомендация экспертной группы применять данное вмешательство только у пациентов, затронутых наивысшим риском, может обострить неравенство в области здравоохранения. С другой стороны, принимая во внимание доказанные преимущества для пациентов и по-прежнему слабый охват вакцинацией в некоторых СНСД и странах с низким уровнем дохода, сотровимаб может быть полезным инструментом для сокращения госпитализации, вызванной COVID-19, среди невакцинированного населения. Кроме того, данные рекомендации должны обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этому средству лечения. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Семнадцатого декабря 2021 г. ВОЗ опубликовала Седьмое приглашение для производителей лекарственных средств для лечения COVID-19 к подаче предварительных заявок на участие в оценке продукции, в том числе сотровимаба, в Департамент преквалификации ВОЗ. Обоснование Рассмотренные в совокупности фактические данные, ценностные ориентиры и предпочтения, а также вопросы практического осуществления легли в основу условной рекомендации использовать сотровимаб только у пациентов с нетяжелым течением COVID-19, подвергающихся наиболее высокому риску госпитализации. К типичным характеристикам лиц, затронутых наивысшим риском, могут быть отнесены отсутствие вакцинации, пожилой возраст или наличие иммунодефицитных состояний и/или хронических заболеваний (например, диабета). Несмотря на наличие фактических данных средней степени убедительности, указывающих на существенное снижение относительного риска госпитализации, вероятно, лишь меньшинство пациентов, относящихся к группе наиболее высокого риска, получат значимую пользу от применения данного вмешательства, которая позволит компенсировать риски и другие ограничения и недостатки данного лечения. К ним относятся отсутствие надежных инструментов для выявления пациентов, затронутых высоким риском, предоставление парентеральных терапевтических средств пациентам, обычно получающим помощь на базе общин, и ограниченная доступность препарата. 65 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Значение сотровимаба и комбинации казиривимаба и имдевимаба Еще одна комбинация моноклональных антител, казиривимаба и имдевимаба также условно рекомендуется пациентам с нетяжелым течением COVID-19, которые затронуты наивысшим риском госпитализации. Группа по разработке руководящих принципов рекомендовала клиницистам избегать совместного введения данных препаратов в связи с отсутствием фактических сведений о синергетическом эффекте при таком назначении, а также в связи с низкой вероятностью автоматического достижения синергетического эффекта. Кроме того, группа рассмотрела порядок выбора одного из двух препаратов. Прямые сравнения не проводились ни в одном из испытаний. По данным косвенного сравнения на основе ОДСМА (см. сводную таблицу результатов наблюдений в соответствии с методологией GRADE в разделе со сведениями по итогам исследования), взаимосвязь приема конкретного лекарственного средства с важнейшими исходами при заражении пациента вариантом «альфа» или «дельта» может быть одинаковой в обоих случаях либо различаться в минимальной степени. В настоящее время и в дальнейшем выбор моноклональных антител будет зависеть от поступающих сведений об эффективности этих средств в отношении различных вариантов вируса, доступности этих средств, а также клинических факторов и обстоятельств на местах. Необходимо заметить, что РКИ, включенные в ОДСМА, проводились до появления варианта вируса «омикрон». После опубликования предыдущей условной рекомендации в отношении комбинации казиривимаба и имдевимаба появились доклинические данные, свидетельствующие о том, что эта комбинация моноклональных антител не обладает нейтрализующей активностью против варианта «омикрон» in vitro (71). Недавние данные доклинических исследований свидетельствуют о том, что нейтрализующее действие сотровимаба в отношении все более широко распространяющегося варианта вируса «омикрон» ВА.2 существенно снижено (см. «Механизм действия»). В отсутствие клинических данных влияние на эффективность сотровимаба остается неустановленным, и в настоящее время группа по разработке руководящих принципов проводит анализ данной проблемы. Возможность применения Дети и беременные женщины. Во включенные РКИ проводился набор взрослых пациентов за исключением беременных; таким образом, применимость для детей и беременных женщин остается невыясненной. Группа по разработке руководящих принципов не имела оснований предполагать, что ответ на лечение сотровимабом у детей или беременных женщин, страдающих COVID-19, будет отличаться. Вместе с тем риск госпитализации у детей, как правило, крайне низок, и группа по разработке руководящих принципов пришла к выводу о том, что при отсутствии иммуносупрессии или другого значимого фактора риска детям не следует проводить данное вмешательство. Пациенты с тяжелым и крайне тяжелым течением COVID-19. В одном из РКИ была проведена рандомизация 546 взрослых, госпитализированных с COVID-19, в одну из двух групп лечения нейтрализующими моноклональными антителами (сотровимаб и BRII-196 плюс BRII-198) или плацебо (73). По результатам не было выявлено преимуществ терапии данными антителами, в том числе в ходе сравнительного анализа в подгруппах пациентов с серопозитивным и серонегативным статусом. Хотя роль сотровимаба при лечении тяжелой и крайне тяжелой формы COVID-19 не подтверждается новым исследованием, группа не изучила данные результаты, так как упор в аналитической работе был сделан на доступные на момент подготовки рекомендации материалы, относящиеся к группе лиц с нетяжелым течением COVID-19; итоги данного исследования и любые вновь опубликованные фактические данные будут всесторонне изучены группой при подготовке дальнейших рекомендаций в отношении сотровимаба. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: сотровимаб Сравнение: стандарт оказания помощи Резюме В основу ОДСМА по сотровимабу было положено одно РКИ (COMET-ICE), в которое рандомизировали 1057 негоспитализированных пациентов с манифестной формой COVID-19 (в сроки не более пяти дней от момента дебюта симптомов) и наличием не менее одного фактора риска прогрессирования заболевания. У группы по проведению ОДСМА имелся доступ к данным о 1044 пациентах из 1057. Включенные пациенты были рандомизированы в группу лечения сотровимабом в однократно вводимой дозе 500 мг или плацебо. Медианное значение возраста пациентов составило 53 года; 46% пациентов были мужского пола. Медиана продолжительности катамнестического наблюдения в популяции с назначенным лечением составила 72 дня. Вакцинированные пациенты были исключены из исследования (74). В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения сотровимаба для лечения пациентов с COVID-19 по сравнению со стандартом оказания помощи (плацебо) в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. Анализ в подгруппах Группа запросила проведение анализа в четырех заранее определенных подгруппах: 1. Возраст: дети в сравнении со взрослыми (моложе 70 лет) и лицами старшего возраста (70 лет и старше). 2. Тяжесть течения заболевания (на момент начала лечения): нетяжелое по сравнению с тяжелым и крайне тяжелым течением. 3. Сроки появления симптомов. 4. Серологический статус. В исследовании не имелось данных для проведения указанной аналитической работы. 66 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство Сотровимаб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,11 (95% ДИ: 0–2,6) Данные по 1044 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 6 на 1000 1 на 1000 Средняя Ввиду крайне косвенного характера данных и неоднозначности их трактовки1 Предположительно, сотровимаб оказывает слабое влияние либо не оказывает влияние на показатель смертности. Разница: сокращение на 5 случаев на 1000 (95% ДИ: сокращение на 6 случаев – увеличение на 9 случаев) Искусственная вентиляция легких Отношение шансов: 0,11 (95% ДИ: 0–2,6) Данные по 1044 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 8 на 1000 1 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных2 Предположительно, влияние сотровимаба на потребность в искусственной вентиляции легких минимально или отсутствует. Разница: сокращение на 7 случаев на 1000 (95% ДИ: сокращение на 8 случаев – увеличение на 13 случаев) Госпитализация Риск в исследованиях Отношение шансов: 0,19 (95% ДИ: 0,06–0,51) Данные по 1044 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 35 на 1000 7 на 1000 Средняя Ввиду крайне косвенного характера данных3 Вероятно, применение сотровимаба приводит к сокращению госпитализации. Разница: сокращение на 28 случаев на 1000 (95% ДИ: сокращение на 33 случая – сокращение на 17 случаев) Госпитализация Крайне высокий риск Отношение шансов: 0,19 (95% ДИ 0,06–0,51) на основании данных о 1044 участниках в 1 исследовании (рандомизированные контролируемые) 60 на 1000 12 на 1000 Средняя Ввиду крайне косвенного характера данных4 Вероятно, применение сотровимаба приводит к сокращению госпитализации. Разница: сокращение на 48 случаев на 1000 (95% ДИ: сокращение на 56 случаев – сокращение на 28 случаев) Госпитализация Наивысший риск Отношение шансов: 0,19 (95% ДИ: 0,06–0,51) Данные по 1044 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 100 на 1000 21 на 1000 Средняя Ввиду крайне косвенного характера данных5 Вероятно, применение сотровимаба приводит к сокращению госпитализации. Разница: сокращение на 79 случаев на 1000 (95% ДИ: сокращение на 93 случая – сокращение на 46 случаев) Инфузионные реакции На основании данных по 1044 пациентам в 1 исследовании (рандомизированные контролируемые) 0 на 1000 0 на 1000 Высокая Применение сотровимаба практически не влияет на инфузионные реакции. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 13 случаев – увеличение на 13 случаев) Время до исчезновения симптомов Нет данных Влияние сотровимаба не определено. 1. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение сотровимаба может оказать существенное влияние на потребность в искусственной вентиляции легких. Неоднозначность трактовки данных: несущественная. Всего было зарегистрировано четыре случая летального исхода (все в группе плацебо) в единственном исследовании, посвященном изучению сотровимаба. 2. Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. У этих пациентов применение сотровимаба может оказать существенное влияние на потребность в искусственной вентиляции легких. Неоднозначность трактовки данных: существенная. Крайне малое количество событий – инвазивная искусственная вентиляция легких проводилась только четырем пациентам в одном исследовании (все в группе плацебо). 67 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 3. Неоднозначность трактовки данных: существенная. Малое количество событий (всего 25: 4 в группе лечения сотровимабом и 21 в группе плацебо); не соответствует оптимальному объему информации. 4. Неоднозначность трактовки данных: существенная. Малое количество событий (всего 25: 4 в группе лечения сотровимабом и 21 в группе плацебо); не соответствует оптимальному объему информации. 5. Неоднозначность трактовки данных: существенная. Малое количество событий (всего 25: 4 в группе лечения сотровимабом и 21 в группе плацебо); не соответствует оптимальному объему информации. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: Сотровимаб Сравнение: комбинация казиривимаба и имдевимаба Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение комбинация казиривимаба и имдевимаба Вмешательство Сотровимаб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Искусственная вентиляция легких Отношение шансов: 0 (95% ДИ: 0–0,01) (рандомизированные контролируемые) 2 на 1000 0 на 1000 Средняя Ввиду крайне косвенного характера данных и определенной неоднозначности1 Предположительно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует. Разница: сокращение на 2 случая на 1000 (95% ДИ: сокращение на 2 случая – сокращение на 2 случая) Смертность Отношение шансов: 0,53 (95% ДИ: 0,09–2,12) (рандомизированные контролируемые) 3 на 1000 2 на 1000 Средняя Ввиду крайне косвенного характера данных и определенной неоднозначности2 Предположительно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует. Разница: сокращение на 1 случай на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 3 случая) Госпитализация Группа крайне высокого риска Отношение шансов: 0,68 (95% ДИ: 0,21–1,97) (рандомизированные контролируемые) 18 на 1000 12 на 1000 Средняя Ввиду крайне косвенного характера данных и определенной неоднозначности3 Предположительно, влияние на потребность в госпитализации минимально или отсутствует. Разница: сокращение на 6 случаев на 1000 (95% ДИ: сокращение на 14 случаев – увеличение на 17 случаев) Инфузионные реакции 0 на 1000 0 на 1000 Высокая Возможно, влияние на частоту инфузионных реакций минимально или отсутствует. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 13 случаев – увеличение на 13 случаев) Госпитализация Группа наивысшего риска Отношение шансов: 0,68 (95% ДИ: 0,21–1,97) (рандомизированные контролируемые) 31 на 1000 21 на 1000 Средняя Ввиду крайне косвенного характера данных и определенной неоднозначности4 Предположительно, влияние на потребность в госпитализации минимально или отсутствует. Разница: сокращение на 10 случаев на 1000 (95% ДИ: сокращение на 24 случая – увеличение на 28 случаев) Госпитализация Риск в исследованиях Отношение шансов: 0,68 (95% ДИ: 0,21–1,97) (рандомизированные контролируемые) 10 на 1000 7 на 1000 Средняя Ввиду крайне косвенного характера данных и определенной неоднозначности5 Предположительно, влияние на потребность в госпитализации минимально или отсутствует. Разница: сокращение на 3 случая на 1000 (95% ДИ: сокращение на 8 случаев – увеличение на 10 случаев) Время до клинического улучшения состояния Нет данных Влияние сотровимаба не определено. • Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель потребности в искусственной вентиляции легких будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. Наличие важных различий по критерию потребности в искусственной вентиляции легких в данной категории пациентов остается неопределенным. Неоднозначность трактовки данных: несущественная. Крайне малое количество событий – инвазивная искусственная вентиляция легких проводилась только двум пациентам в одном исследовании (оба в группе плацебо). 68 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) • Косвенный характер данных: существенный. Исходный риск для популяции в целом крайне низок, то есть влияние на показатель смертности будет крайне низким. Существуют группы лиц, которые затронуты более высоким исходным риском и выявление которых затруднено. Для данных пациентов влияние на параметр смертности не определено Неоднозначность трактовки данных: несущественная. Всего был зарегистрирован один случай летального исхода (в группе плацебо) в единственном исследовании, посвященном изучению сотровимаба. • Косвенный характер данных: существенный. Выявление пациентов, затронутых высоким риском, затруднено. Неоднозначность трактовки данных: несущественная. • Косвенный характер данных: существенный. Выявление пациентов, затронутых высоким риском, затруднено. Неоднозначность трактовки данных: несущественная. • Косвенный характер данных: существенный. Выявление пациентов, затронутых высоким риском, затруднено. Неоднозначность трактовки данных: несущественная. 6.8.1. Механизм действия Сотровимаб (VIR-7831; GSK4182136) является препаратом моноклональных антител одного вида, связывающихся с консервативным эпитопом спайк-белка вируса SARS-CoV-2, что препятствует проникновению вируса в клетки. Сотровимаб является моноклональным антителом класса IgG с модифицированным Fc-фрагментом, время полужизни которого, как полагают, больше, чем у немодифицированных моноклональных антител класса IgG, однако общедоступных сведений о времени полужизни при использовании у человека не имеется. Опубликованные сведения доклинических исследований или изучения фармакокинетики у человека на момент выполнения обзора отсутствовали, в связи с чем оценка была выполнена на основе обнародованных сведений регулирующих органов и фармакопейной статьи компании GSK (75). В модели инфекции, вызванной вирусом SARS-CoV-2, с использованием переднеазиатских хомяков показано, что противовирусная активность достигается в концентрации 5 мг/кг при внутрибрюшинном введении антитела без модификации Fc-фрагмента (75). Нейтрализация вируса SARS-CoV-2 (USA WA1/2020) достигалась в линии клеток Vero E6 при значении EC90 на уровне 0,19 мкг/мл (76). Сывороточные концентрации сотровимаба в исследовании COMET-ICE (однократное введение 500 мг внутривенно) позволили обеспечить среднее геометрическое значение Cmax (по истечении 1 часа после в/в инфузии) на уровне 117,6 мкг/мл (N=129, CV% 40) и среднее геометрическое сывороточной концентрации на 29 день на уровне 24,5 мкг/мл (76). Таким образом, ожидается, что по прошествии 29 дней сывороточная концентрация в популяции в среднем будет в 129 раз превышать концентрацию, необходимую в лабораторных условиях для нейтрализации исходного штамма вируса SARS-CoV-2. По данным обзорной публикации авторов из компании "Vir Biotechnology", нейтрализующая активность сотровимаба для всех протестированных вариантов вируса, вызывающих обеспокоенность, в число которых в указанное время не входил вариант «омикрон», снижается менее чем в 10 раз (77). Кроме того, по информации, содержащейся в разрешении FDA на использование в чрезвычайной ситуации, в тестах с нейтрализацией вирусоподобных частиц различных псевдотипов «не выявлено изменений» активности сотровимаба в отношении вариантов вируса «альфа», «бета», «гамма», «эпсилон», «иота», «каппа», «дельта» (в том числе с мутацией K417N), «лямбда» и «мю» (76). В исследованиях с использованием псевдовирусной тест-системы показано, что сотровимаб сохраняет активность в отношении варианта «омикрон», однако для нейтрализации необходимо применение более высоких концентраций, чем для вируса дикого типа (72). В ряде публикаций показано, что нейтрализация сублинии ВА.2 варианта вируса «омикрон» снижена в большей степени, чем нейтрализация сублинии ВА.1 (79)(78) (https://www.biorxiv.org/ content/10.1101/2021.03.09.434607v10). Для более полного понимания взаимосвязи фармакокинетических и фармакодинамических параметров будет необходимо определить, каким образом данное снижение активности влияет на эффективность сотровимаба. Под воздействием давления естественного отбора при использовании сотровимаба в структуре консервативного эпитопа спайк-белка в культуре клеток быстро возникла аминокислотная замена E340A, и последующие результаты тестирования с использованием псевдовирусной системы выявили более чем 100-кратное снижение чувствительности к сотровимабу (76). Кроме того, описаны шестнадцать других замен, интродуцированных в эпитоп, которые приводили к снижению эффективности нейтрализации при помощи сотровимаба в 5,4 – более чем 297 раз (76). Таким образом, в эксперименте может быть получено возникновение устойчивости к сотровимабу. Кроме того, сообщается, что среди первой группы из 1000 пациентов, которым было назначено лечение сотровимабом в ходе распространения варианта «дельта» в Австралии, в четырех случаях была выявлена мутация Е340 генетической последовательности вируса, а также положительный результат культурального исследования по прошествии 12–24 дней после получения препарата (80). 69 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.9. Плазма реконвалесцентов (опубликовано 7 декабря 2021 г.) Справочная информация Рекомендации по применению плазмы реконвалесцентов для лечения пациентов с нетяжелым, тяжелым и крайне тяжелым течением COVID-19 были опубликованы 7 декабря 2021 г. в седьмой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Рекомендации были выпущены в рамках ОДСМА, посвященного терапии с использованием антител и клеток, после опубликования результатов 16 РКИ, в которых изучалась различная тяжесть заболевания (2). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся плазмы реконвалесцентов, внесено не было. Для пациентов с нетяжелым течением COVID-19 Практические сведения Группа по разработке руководящих принципов вынесла настоятельную рекомендацию не применять плазму реконвалесцентов для лечения пациентов с нетяжелым течением COVID-19 и рекомендацию не применять плазму реконвалесцентов для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19, за исключением случаев проведения клинических испытаний. С учетом вышесказанного в настоящих рекомендациях не будут подробно рассматриваться многие практические вопросы, связанные с клиническим использованием плазмы реконвалесцентов, включая, в том числе, отбор и привлечение потенциальных доноров, заготовку плазмы, ее хранение и распределение, а также трансфузию реконвалесцентной плазмы реципиентам. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Назначение реконвалесцентной плазмы пациентам с нетяжелым течением заболевания не оказывает значимого влияния на уровень смертности. Применение реконвалесцентной плазмы предположительно не приводит к снижению потребности в искусственной вентиляции легких. В связи с отсутствием данных в отношении риска госпитализации на фоне применения плазмы реконвалесцентов влияние этого лечебного вмешательства на уровень госпитализации остается крайне неопределенным. Применение плазмы реконвалесцентов предположительно не приводит к значимому повышению риска развития острого посттрансфузионного повреждения легких (TRALI-синдром), циркуляторной перегрузки, вызванной трансфузией (TACO-синдром), или аллергических реакций. Убедительность фактических данных Фактические данные по влиянию данного вмешательства на уровень смертности имели высокую степень убедительности, а по влиянию на потребность в искусственной вентиляции легких – среднюю степень убедительности в связи с высокой вероятностью систематической ошибки. Степень убедительности фактических данных в отношении частоты развития острого посттрансфузионного повреждения легких и циркуляторной перегрузки, вызванной трансфузией, была оценена как средняя в связи с высокой вероятностью систематической ошибки, а в отношении аллергических реакций – как средняя ввиду вероятности систематической ошибки и неоднозначности трактовки данных. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что с учетом имеющихся фактических данных по соотношению пользы и вреда практически все надлежащим образом информированные пациенты будут склонны отказаться от применения донорской плазмы реконвалесцентов. К другим важным с точки зрения популяции аспектам, которые были приняты во внимание, относились практическая осуществимость, приемлемость, обеспечение равноправного доступа и ценовые соображения (см. раздел 7). По мнению группы по разработке руководящих принципов, использование плазмы реконвалесцентов у пациентов с нетяжелой формой заболевания будет сопряжено с дополнительными трудностями в связи с необходимостью обеспечения ресурсов и практической реализации вмешательства в амбулаторных условиях, и возможность широкого применения реконвалесцентной плазмы на практике представляется сомнительной. Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Группа по разработке руководящих принципов отметила, что применение плазмы реконвалесцентов требует значительных Настоятельная рекомендация не применять Новые сведения Не рекомендуется лечение с использованием плазмы реконвалесцентов (настоятельная рекомендация не применять). 70 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) ресурсных затрат на отбор потенциальных доноров, тестирование доноров с целью подтверждения достаточного титра антител к SARS-CoV-2, заготовку донорской плазмы, ее хранение и транспортировку к месту нахождения реципиента, а также введение плазмы пациенту. Указанные сложности ресурсообеспечения и практической реализации усугубляются в случае пациентов с нетяжелым течением заболевания, которые чаще всего лечатся амбулаторно. Кроме того, данный процесс является дорогостоящим и занимает много времени. Принимая во внимание большое количество пациентов с нетяжелой формой заболевания и низкую частоту неблагоприятных клинических исходов в этой подгруппе, мобилизация широкого использования плазмы реконвалесцентов в практической работе представляется сомнительной. Хотя переливание крови является приемлемым лечебным вмешательством для большинства пациентов, существует подгруппа населения, которая не будет склонна согласиться на переливание аллогенной крови. Кроме того, в большинстве стран переливание продуктов крови связано с необходимостью выполнения ряда нормативных требований. Обоснование Рассмотренные в совокупности фактические данные, ценностные ориентиры и предпочтения, а также вопросы практического осуществления легли в основу настоятельной рекомендации не применять плазму реконвалесцентов для лечения пациентов с нетяжелым течением COVID-19. Важнейшим соображением является то, что с учетом отсутствия каких-либо доказанных преимуществ в отношении любого из крайне важных или важных клинических исходов как при нетяжелом, так и при тяжелом/крайне тяжелом течении COVID-19, группа по разработке руководящих принципов не видит оснований для задействования ресурсов (включая временные и финансовые), необходимых для организации процесса по переливанию реконвалесцентной плазмы. При вынесении этой рекомендации также учитывались возможные риски данного лечебного вмешательства (несмотря на отсутствие соответствующих доказательств в резюме фактических данных, такую возможность при переливании препаратов крови исключить нельзя), низкий исходный риск летального исхода, потребности в искусственной вентиляции легких и госпитализации при нетяжелых формах инфекции, а также практические трудности, связанные с введением плазмы. Титры антител Показатели титров нейтрализующих антител существенно различались между исследованиями, при этом более чем в половине исследований не сообщалось о титрах антител у реципиентов либо соответствующие показатели не учитывались. Более того, в самом крупном исследовании (RECOVERY) не было представлено никаких сведений об титрах антител в донорской плазме. Даже при наличии такой информации методы тестирования и объемы трансфузии были разными. Указанные ограничения не позволили провести анализ на основании уровня титра антител в донорской плазме или оценить достоверность эффектов, наблюдаемых в подгруппах. Возможность применения Поскольку во всех рассмотренных РКИ участвовали взрослые пациенты, за исключением беременных женщин, применимость данной рекомендации к детям и беременным женщинам остается невыясненной. Группа по разработке руководящих принципов не имела оснований предполагать, что ответ на лечение плазмой реконвалесцентов у детей, страдающих COVID-19, будет отличаться. С другой стороны, риск госпитализации у детей, как правило, крайне низок, и группа по разработке руководящих принципов пришла к выводу о том, что при отсутствии иммуносупрессии или другого значимого фактора риска детям не следует проводить данное вмешательство. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: плазма реконвалесцентов Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных по плазме реконвалесцентов использовали ОДСМА 16 РКИ с участием 16 236 пациентов с нетяжелым, тяжелым и крайне тяжелым течением заболевания. Все включенные РКИ были зарегистрированными, при этом 80% были опубликованы в рецензируемых научных журналах, а 20% доступны в форме предварительной публикации. Практически все участники исследования (99%) находились на лечении в стационаре; из них 15% были госпитализированы в отделение реанимации и интенсивной терапии (ОРИТ). Один процент пациентов был набран в амбулаторных условиях. Ни в одном из включенных исследований не участвовали дети или беременные женщины. В таблице представлены характеристики соответствующих РКИ, при этом в двух исследованиях сравнение с плазмой проводилось в отношении плацебо, и они не были включены в резюме фактических данных. Группе по разработке руководящих принципов известно о двух других опубликованных РКИ, в которых проводилось сравнение применения плазмы реконвалесцентов со стандартным лечением или плацебо (81)(82). Результаты этих исследований не были учтены в последнем представленном экспертной группе анализе, на основании которого были вынесены рекомендации. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения реконвалесцентной плазмы для лечения пациентов с нетяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. При составлении резюме фактических данных использовались ОДСМА (2), в которых были объединены данные по смертности, полученные в четырех РКИ с участием 1602 пациентов, и меньший объем данных по другим исходам, за исключением аллергических реакций (8 РКИ, 243 пациента). В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. 71 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Анализ в подгруппах Экспертной группой было запланировано проведение анализа данных в подгруппах, выделенных по следующим критериям: 1. Возраст: взрослые пациенты молодого возраста (моложе 70 лет) по сравнению с лицами старшего возраста старше 70 лет). 2. Тяжесть течения заболевания (на момент начала лечения): нетяжелое по сравнению с тяжелым и крайне тяжелым течением. 3. Лечебная доза: плазма с высоким титром антител по сравнению с плазмой с низким титром антител. Анализ в подгруппах выполнен для пациентов со всеми формами заболевания. Ввиду недостаточного объема данных по большинству подгрупп в отношении интересующих исходов проведение анализа в подгруппах не было возможным. Результаты выполненного анализа в тех подгруппах, по которым имелись данные, свидетельствовали об отсутствии значимого влияния данного вмешательства на уровень смертности в подгруппах, выделенных на основе тяжести заболевания (p=0,80) и возраста (p=0,84), а также на потребность в искусственной вентиляции легких в подгруппах пациентов с различной тяжестью заболевания (p=0,17). Исход Период времени Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Плазма реконвалесцентов Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность ближе к 90 дням Отношение шансов: 0,83 (95% ДИ: 0,43–1,46) Данные по 1602 пациентам, полученные в 4 исследованиях1 (рандомизированные контролируемые) 3 на 1000 2 на 1000 Высокая2 Назначение реконвалесцентной плазмы не оказывает значимого влияния на уровень смертности. Разница: сокращение на 1 случай на 1000 (95% ДИ: сокращение на 2 случая – увеличение на 1 случай) Искусственная вентиляция легких ближе к 90 дням Отношение шансов: 0,71 (95% ДИ: 0,18–1,77) Данные по 705 пациентам, полученные в 3 исследованиях3 (рандомизированные контролируемые) 6 на 1000 4 на 1000 Средняя Ввиду высокой вероятности систематической ошибки4 Применение реконвалесцентной плазмы предположительно не приводит к снижению потребности в искусственной вентиляции легких. Разница: сокращение на 2 случая на 1000 (95% ДИ: сокращение на 5 случаев – увеличение на 5 случаев) Острое посттрансфузи онное повреждение легких (TRALI- синдром) в течение 28 дней Данные по 1365 пациентам, полученные в 4 исследованиях5 (рандомизированные контролируемые) 0 на 1000 0 на 1000 Средняя Ввиду высокой вероятности систематической ошибки6 Вероятно, применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития острого посттрансфузионного повреждения легких. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 5 случаев – увеличение на 6 случаев) Циркуляторная перегрузка, вызванная трансфузией (TACO- синдром) в течение 28 дней Данные по 1442 пациентам, полученные в 4 исследованиях7 (рандомизированные контролируемые) 0 на 1000 5 на 1000 Средняя Ввиду высокой вероятности систематической ошибки8 Предположительно, применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития циркуляторной перегрузки, вызванной трансфузией. Разница: увеличение на 5 случаев на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 12 случаев) Аллергические реакции в срок 28 дней Отношение шансов: 3,25 (95% ДИ: 1,27–9,3) Данные по 15 243 пациентам, полученные в 8 исследованиях9 (рандомизированные контролируемые) 3 на 1000 10 на 1000 Низкая Ввиду вероятности систематической ошибки и неоднозначности трактовки данных10 Вероятно, применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития аллергических реакций. Разница: увеличение на 7 случаев на 1000 (ДИ 95% увеличение на 1 случай – увеличение на 24 случая) 72 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [87], [83], [84], [86], 2. Риск систематической ошибки: серьезный риск отсутствует. Группа по разработке руководящих принципов не стала понижать степень убедительности данных из-за риска систематической ошибки, связанной с отсутствием маскировки данных. 3. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [83], [84], [87], 4. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: несущественная. Группа по разработке руководящих принципов не стала понижать степень убедительности данных из-за неоднозначности трактовки данных, поскольку как важные преимущества, так и серьезный вред не попадают в доверительный интервал. 5. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [88], [84], [89], [85], 6. Риск систематической ошибки: существенный. Большинство пациентов были набраны в исследования, в которых метод маскировки данных не применялся. Неоднозначность трактовки данных: несущественная. Группа по разработке руководящих принципов приняла решение не понижать степень убедительности данных из-за неоднозначности трактовки данных, поскольку важные преимущества не попадают в доверительный интервал, а уровень исходного риска крайне низок. 7. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [89], [85], [83], [88], 8. Риск систематической ошибки: существенный. Большинство пациентов были набраны в исследования, в которых метод маскировки данных не применялся. Неоднозначность трактовки данных: несущественная. Группа по разработке руководящих принципов приняла решение не понижать степень убедительности данных из- за неоднозначности трактовки данных, поскольку важные преимущества не попадают в доверительный интервал, а уровень исходного риска крайне низок. 9. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [92], [88], [86], [83], [91], [85], [89], [90], 10. Риск систематической ошибки: существенный. Риск систематической ошибки был низким в двух исследованиях (491 пациент; 3% от общего числа пациентов), в то время как в шести исследованиях (с участием 14 910 пациентов) – высоким. Неоднозначность трактовки данных: существенная. Экспертная группа признала, что нежелательный эффект в виде повышения частоты аллергических реакций попадает в доверительный интервал, но согласилась с тем, что исходный риск является низким. Для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Группа по разработке руководящих принципов вынесла рекомендацию не применять плазму реконвалесцентов для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19, за исключением случаев проведения клинических испытаний, и настоятельную рекомендацию не применять плазму реконвалесцентов для лечения пациентов с нетяжелым течением COVID-19. С учетом вышесказанного в настоящих рекомендациях не будут подробно рассматриваться многие практические вопросы, связанные с клиническим использованием плазмы реконвалесцентов, включая, в том числе, отбор и привлечение потенциальных доноров, заготовку плазмы, ее хранение и распределение, а также трансфузию реконвалесцентной плазмы реципиентам. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Применение реконвалесцентной плазмы для лечения пациентов с тяжелым/крайне тяжелым течением заболевания может не оказывать значимого влияния на уровень смертности, потребность в искусственной вентиляции легких, продолжительность времени до появления клинического улучшения, продолжительность пребывания в стационаре или количество дней без пребывания на искусственной вентиляции легких. Применение плазмы реконвалесцентов, вероятно, не приводит к значимому повышению риска развития острого посттрансфузионного повреждения легких (TRALI-синдром), циркуляторной перегрузки, вызванной трансфузией (TACO- синдром), или аллергических реакций. Вместе с тем, несмотря на отсутствие соответствующих доказательств в резюме фактических данных, при переливании препаратов крови нельзя полностью исключать возможность развития побочных явлений. Только в условиях проведения исследований Новые сведения Авторы не рекомендуют применение флувоксамина за исключением случаев клинических испытаний (рекомендуется применять только в рамках научных исследований). 73 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Убедительность фактических данных Фактические данные по влиянию данного вмешательства на уровень смертности имели низкую степень убедительности ввиду косвенного характера данных, неоднозначности их трактовки и риска систематической ошибки. Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных до низкой в отношении потребности в искусственной вентиляции легких, продолжительности пребывания в стационаре и количества дней без пребывания на искусственной вентиляции легких ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных, а в отношении продолжительности времени до появления клинического улучшения – в связи с крайней неоднозначностью трактовки данных. Степень убедительности фактических данных в отношении частоты развития острого посттрансфузионного повреждения легких и циркуляторной перегрузки, вызванной трансфузией, была оценена как средняя в связи с высокой вероятностью систематической ошибки, а в отношении аллергических реакций – как средняя ввиду вероятности систематической ошибки и неоднозначности трактовки данных. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что с учетом имеющихся фактических данных по соотношению пользы и вреда практически все надлежащим образом информированные пациенты будут склонны отказаться от применения донорской плазмы реконвалесцентов. К другим важным с точки зрения популяции аспектам, которые были приняты во внимание, относились практическая осуществимость, приемлемость, обеспечение равноправного доступа и ценовые соображения (см. раздел 7). Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Группа по разработке руководящих принципов отметила, что применение плазмы реконвалесцентов требует значительных ресурсных затрат на отбор потенциальных доноров, тестирование доноров с целью подтверждения достаточного титра антител к SARS-CoV-2, заготовку донорской плазмы, ее хранение и транспортировку к месту нахождения реципиента, а также введение плазмы пациенту. Кроме того, данный процесс является дорогостоящим и занимает много времени. Хотя переливание крови является приемлемым лечебным вмешательством для большинства пациентов, существует подгруппа населения, которая не будет склонна согласиться на переливание аллогенной крови. Кроме того, в большинстве стран переливание продуктов крови связано с необходимостью выполнения ряда нормативных требований. Обоснование После всестороннего обсуждения данного вопроса группа приняла решение вынести рекомендацию против применения плазмы реконвалесцентов для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 за исключением случаев клинических испытаний. Принимая во внимание низкую степень убедительности фактических данных, свидетельствующих о том, что применение плазмы реконвалесцентов влияет незначительно либо совсем не влияет на показатель смертности, потребность в искусственной вентиляции легких и продолжительность времени до клинического улучшения состояния и вместе с тем несет в себе риски возникновения негативных побочных эффектов (несмотря на отсутствие соответствующих доказательств в резюме фактических данных, такую возможность при переливании препаратов крови исключить невозможно), экспертная группа высказала мнение о целесообразности дальнейшего изучения эффекта данного вмешательства в отношении этих важных для пациентов исходов. Решение сосредоточить исследования на подгруппе пациентов с тяжелым/крайне тяжелым течением COVID-19 было также обусловлено возможностями практической реализации (такие пациенты уже госпитализированы) и уровнем исходного риска наступления летального исхода и потребности в поддержании жизненно важных функций организма (выше при тяжелом/крайне тяжелом течении COVID-19). Экспертная группа определила, что наиболее приоритетными задачами будущих исследований являются изучение применения плазмы с высоким титром антител, а также учет сведений о титре антител в донорской плазме и объеме произведенной трансфузии, необходимых для получения представления об уровне снижения титров антител у реципиента. Кроме того, группа экспертов выделила в качестве наиболее приоритетного направления будущих исследований вопросы применения реконвалесцентной плазмы у серонегативных пациентов с COVID-19. Рекомендация использовать препарат исключительно в условиях клинических испытаний целесообразна в том случае, если на фоне фактических данных низкой степени убедительности планируется проведение научных изысканий, обладающих потенциалом для уточнения эффектов искомого вмешательства при разумных издержках. 74 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: Пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: Плазма реконвалесцентов Сравнение: стандарт оказания помощи Резюме Резюме фактических данных в отношении плазмы реконвалесцентов Резюме фактических данных представлено в разделе, посвященном подгруппе пациентов с нетяжелым течением COVID-19. В нем приводятся подробные сведения об ОДСМА и 16 включенных исследованиях с участием пациентов с различной тяжестью заболевания, а также результаты анализа в подгруппах, не выявившем достоверных эффектов в зависимости от возраста, тяжести заболевания или использованной дозы реконвалесцентной плазмы. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения реконвалесцентной плазмы для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. При составлении резюме фактических данных использовались ОДСМА (2), в которых были объединены данные по смертности, полученные в десяти РКИ с участием 14 366 пациентов, и меньший объем данных по другим исходам. Оценка риска в исходный момент времени Для оценки важного показателя смертности в группе пациентов с тяжелым и крайне тяжелым течением заболевания был взят оценочный показатель исходного риска наступления летального исхода, равный 13% (130 случаев на 1000 пациентов). Как и в отношении других соответствующих рекомендаций, представленных в данном документе, величина исходного риска смертности заимствована из исследования SOLIDARITY для пациентов с тяжелой и крайне тяжелой формами COVID-19 с внесением поправки на лечебный эффект применения кортикостероидов. При оценке исходного риска наступления других исходов группа по разработке руководящих принципов использовала медианное значение соответствующего показателя в контрольной группе РКИ, данные которых включались в анализ (см. раздел 7). Анализ в подгруппах Экспертной группой было запланировано проведение анализа данных в подгруппах, выделенных по следующим критериям: 1. Возраст: взрослые пациенты молодого возраста (моложе 70 лет) по сравнению с лицами старшего возраста старше 70 лет). 2. Тяжесть течения заболевания (на момент начала лечения): нетяжелое по сравнению с тяжелым и крайне тяжелым течением. 3. Лечебная доза: плазма с высоким титром антител по сравнению с плазмой с низким титром антител. Ввиду недостаточного объема данных по большинству подгрупп в отношении интересующих исходов проведение анализа в подгруппах не было возможным. Результаты выполненного анализа в тех подгруппах, по которым имелись данные, свидетельствовали об отсутствии значимого влияния данного вмешательства на уровень смертности в подгруппах, выделенных на основе тяжести заболевания (p=0,80) и возраста (p=0,84), а также на потребность в искусственной вентиляции легких в подгруппах пациентов с различной тяжестью заболевания (p=0,17). Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство Плазма реконвалесцентов Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность ближе к 90 дням Отношение шансов: 0,92 (95% ДИ: 0,7–1,12) Данные по 14 366 пациентам, полученные в 10 исследованиях1 (рандомизированные контролируемые) 130 на 1000 121 на 1000 Крайне низкая Ввиду косвенного характера данных, риска систематической ошибки и неоднозначности трактовки2 Использование конвалесцентной плазмы может оказывать слабое или нулевое воздействие на показатель смертности. Разница: сокращение на 9 случаев на 1000 (95% ДИ: сокращение на 35 случаев – увеличение на 13 случаев) Искусственная вентиляция легких ближе к 90 дням Отношение шансов: 0,92 (95% ДИ: 0,46–1,68) Данные по 623 пациентам, полученные в 5 исследованиях3 (рандомизированные контролируемые) 86 на 1000: 80 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных4 По‑видимому, применение реконвалесцентной плазмы не приводит к снижению потребности в искусственной вентиляции легких. Разница: сокращение на 6 случаев на 1000 (95% ДИ: сокращение на 45 случаев – увеличение на 50 случаев) 75 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство Плазма реконвалесцентов Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Острое посттрансфузионное повреждение легких (TRALI-синдром) в течение 28 дней Данные по 1365 пациентам, полученные в 4 исследованиях5 (рандомизированные контролируемые) 0 на 1000: 0 на 1000 Средняя Ввиду высокой вероятности систематической ошибки6 Вероятно, применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития острого посттрансфузионно го повреждения легких. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 5 случаев – увеличение на 6 случаев) Циркуляторная перегрузка, вызванная трансфузией (TACO-синдром) в течение 28 дней Данные по 1442 пациентам, полученные в 4 исследованиях7 (рандомизированные контролируемые) 0 на 1000: 5 на 1000 Средняя Ввиду высокой вероятности систематической ошибки8 Предположительно , применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития циркуляторной перегрузки, вызванной трансфузией. Разница: увеличение на 5 случаев на 1000 (95% ДИ: сокращение на 3 случая – увеличение на 12 случаев) Аллергические реакции в срок 28 дней Отношение шансов: 3,25 (95% ДИ: 1,27–9,3) Данные по 15 243 пациентам, полученные в 8 исследованиях9 (рандомизированные контролируемые) 3 на 1000 10 на 1000 Низкая Ввиду вероятности систематической ошибки и неоднозначности трактовки данных10 Вероятно, применение реконвалесцентной плазмы не приводит к значимому повышению частоты развития аллергических реакций. Разница: увеличение на 7 случаев на 1000 (95% ДИ: увеличение на 1 случай – увеличение на 24 случая) Время до клинического улучшения Предпочтителен более низкий уровень На основании данных по: 472 пациентам в 3 исследованиях11 (рандомизированные контролируемые) 15 (среднее значение) 15 (среднее значение) Низкая Ввиду крайней неоднозначности трактовки данных12 Применение реконвалесцентной плазмы может не оказывать влияния на время до клинического улучшения. Разница: СО: сокращение на 0 (95% ДИ: сокращение на 10,4 случая – увеличение на 33,6 случая) Длительность госпитализации Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 1015 пациентам в 7 исследованиях13 (рандомизированные контролируемые) 11,7 дня (среднее значение) 11 дней (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных14 Применение реконвалесцентной плазмы, вероятно, не оказывает влияния на продолжительность пребывания в стационаре. Разница: СО: сокращение на 0,7 (95% ДИ: сокращение на 2,3 случая – увеличение на 1 случай) Дни без ИВЛ в течение 28 дней Единица измерения: день Предпочтительно более высокое значение На основании данных по: 2859 пациентам в 3 исследованиях15 (рандомизированные контролируемые) 13,7 дня (среднее значение) 13 дней (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных16 Применение реконвалесцентной плазмы, вероятно, не оказывает влияния на количество дней без пребывания на искусственной вентиляции легких. Разница: СО: сокращение на 0,7 (95% ДИ: сокращение на 1,8 случая – увеличение на 0,4 случая) 1. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [89], [93], [95], [92], [90], [88], [94], [86], [96], [91]. 2. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. Как важные преимущества, так и серьезный вред попадают в доверительный интервал. 76 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 3. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [93], [89], [85], [92], [95], 4. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: существенная. Группа по разработке руководящих принципов сочла, что исходя из величины доверительных интервалов достаточно однократного понижения степени убедительности данных ввиду неоднозначности их трактовки. 5. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [85], [89], [84], [88], 6. Риск систематической ошибки: существенный. Большинство пациентов были набраны в исследования, в которых метод маскировки данных не применялся. Неоднозначность трактовки данных: несущественная. Группа по разработке руководящих принципов приняла решение не понижать степень убедительности данных из- за неоднозначности трактовки данных, поскольку важные преимущества не попадают в доверительный интервал, а уровень исходного риска низок. 7. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [88], [83], [89], [85], 8. Риск систематической ошибки: существенный. Большинство пациентов были набраны в исследования, в которых метод маскировки данных не применялся. Неоднозначность трактовки данных: несущественная. Группа по разработке руководящих принципов приняла решение не понижать степень убедительности данных из- за неоднозначности трактовки данных, поскольку важные преимущества не попадают в доверительный интервал, а уровень исходного риска низок. 9. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [91], [85], [89], [83], [92], [88], [90], [86], 10. Риск систематической ошибки: существенный. Риск систематической ошибки был низким в двух исследованиях (491 пациент; 3% от общего числа пациентов), в то время как в шести исследованиях (с участием 14 910 пациентов) – высоким. Неоднозначность трактовки данных: существенная. Экспертная группа признала, что нежелательный эффект в виде повышения частоты аллергических реакций попадает в доверительный интервал, но согласилась с тем, что исходный риск является низким. 11. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [89], 12. Неоднозначность трактовки данных: крайняя. 13. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [93], [88], [94], [95], [96], [92], [89], 14. Риск систематической ошибки: существенный. Во всех исследованиях, кроме одного, не применялся надлежащий метод маскировки данных. Неоднозначность трактовки данных: существенная. Величина доверительных интервалов не позволяет исключить наличия небольшого, но важного преимущества. 15. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [92], [88], [90], 16. Риск систематической ошибки: существенный. Практически все пациенты были рандомизированы в исследования, в которых не применялся метод маскировки данных. Неоднозначность трактовки данных: существенная. Величина доверительных интервалов не позволяет исключить наличия важного преимущества. 6.9.1. Механизм действия Предполагается, что основной механизм действия реконвалесцентной плазмы заключается во введении пациентам с активной инфекцией нейтрализующих антител, содержащихся в донорской плазме пациентов, которые перенесли данную инфекцию ранее и выработали против нее иммунитет (97). Таким образом, вероятная эффективность указанного механизма действия зависит от того, сохраняется ли достаточная концентрация антител после разведения перелитого объема плазмы донора в крови реципиента. В этом случае важную роль играет как титр нейтрализующих антител в плазме донора, так и объем трансфузии. Данные, полученные в модельных испытаниях на переднеазиатских хомяках, свидетельствовали об эффективности применения антиковидной плазмы реконвалесцентов с титром антител 1:2560 и об отсутствии эффекта плазмы с титром 1:320 при введении препарата в объеме 1 мл, что с учетом среднего объема крови соответствует объему дозирования для человека, равному 300 мл (98). Согласно предельным значениям, использованным в исследованиях, в которых изучалось клиническое применение реконвалесцентной плазмы и сообщалось о вводимой дозе с указанием титра нейтрализующих антител и объема трансфузии, введение 200 мл должно было привести к разведению препарата в среднем в 25 раз, а введение 1000 мл – в среднем в 5 раз по сравнению с титрами антител, регистрируемыми в крови самого донора (с учетом того, что средний объем циркулирующей крови человека составляет 5 л (99)). Следует также признать, что уровень концентрации (титр) нейтрализующих антител в реконвалесцентной плазме разных доноров может колебаться в широких пределах и что существуют различные методики для его измерения (100). Кроме того, такие параметры, как титры антител, методология их определения и объем вводимой плазмы, использованные в исследованиях этого подхода к лечению COVID-19, существенно отличаются друг от друга. Следует также принять к сведению, что в некоторых исследованиях титр антител, заявленный как один из критериев отбора доноров, был выше, чем титр антител в использованной донорской плазме, что связано с различием в методологии их измерения в обоих случаях (например, для подтверждения соответствия донора критериям включения в исследование измеряли уровень общего IgG, а в дальнейшем оценивали титр специфических нейтрализующих антител (101)). При этом отмечается явная неопределенность данных в отношении дозы нейтрализующих антител, использованной в различных исследованиях, что в целом можно охарактеризовать следующим образом: 77 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Исследования с участием пациентов с тяжелым/крайне тяжелым течением заболевания • В 9 из 16 исследований не были установлены пороговые значения для титров нейтрализующих антител в плазме донора. • В 12 из 16 исследований титр антител в плазме донора не регистрировали, что означает, что титр мог быть как высоким, так и низким. Однако в трех исследованиях из числа тех, в которых титр антител донора не регистрировали, применяли более низкие пороговые значения для титров антител: либо 1:160 (в двух исследованиях), либо 1:400. • В самом масштабном исследовании (RECOVERY) титр антител доноров не учитывали, хотя критерием участия был титр антител на уровне выше 1:100. • В одном (1/16) исследовании не было предоставлено сведений об объеме вводимой плазмы, то есть объем трансфузии мог быть как большим, так и малым. • Данные об обоих показателях (объем трансфузии и титр антител у донора) имелись только по 6 из 16 исследований. Титры антител в донорской плазме составляли 1:80, 1:87, 1:300, 1:320, 1:526 и 1:640 при объемах трансфузии 300, 500, 400–600, около 480, 750–975 и 300 мл соответственно (по оценкам, дозы в пределах использованного диапазона различаются в 6 раз). Исследования с участием пациентов с нетяжелым течением заболевания • Применение плазмы реконвалесцентов для лечения пациентов с нетяжелым течением заболевания было изучено только в трех исследованиях, в которых использовали плазму с титрами антител 1:40, 1:292 и 1:3200 при объеме трансфузии 250–300 мл, 400 мл и 250 мл соответственно (по оценкам, дозы в пределах использованного диапазона различаются в 100 раз). • В двух исследованиях изучали применение плазмы как при нетяжелых, так и при тяжелых/крайне тяжелых формах инфекции, при этом в одном из них титр антител не определяли, а в другом использовали трансфузию плазмы в объеме 200–250 мл +/– 75 мл с титром антител 1:160. 78 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.10. Комбинация казиривимаба и имдевимаба (нейтрализующие моноклональные антитела) (опубликовано 24 сентября 2021 г.) Справочная информация Рекомендации по применению комбинации нейтрализующих моноклональных антител (казиривимаб и имдевимаб) для лечения пациентов с нетяжелым, тяжелым и крайне тяжелым течением COVID-19 были опубликованы 24 сентября 2021 г. в шестой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Они были подготовлены по результатам предварительно опубликованных данных четырех испытаний, которые проводились в рамках общего адаптивного рандомизированного основного протокола исследований в группе пациентов с нетяжелым течением заболевания, а также опубликованных данных исследования RECOVERY, посвященного вопросам ведения тяжелых и крайне тяжелых случаев заболевания (9)(10)(11). После опубликования предыдущей условной рекомендации в отношении комбинации казиривимаба и имдевимаба поступили новые сведения доклинических исследований (см. раздел «Механизм действия» ) (102). Накоплен существенный объем доклинических лабораторных данных, а также проведена подтверждающая оценка in vivo, которые указывают на недостаточную эффективность комбинации казиривимаба и имдевимаба в отношении варианта «омикрон» ВА.1 (см. раздел «Механизм действия») В связи с этим в настоящее время не рекомендуется применение комбинации казиривимаба и имдевимаба для лечения COVID-19, за исключением ситуаций, в которых доступно оперативное генотипирование вируса и подтверждено заражение вариантом вируса SARS-CoV-2 (таким как вариант «дельта»), который чувствителен к нейтрализующей активности данной комбинации моноклональных антител. Группа подчеркивает, что для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации, имеется ряд альтернатив (см. раздел 6.1 и примечания под текстом рекомендаций). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся плазмы реконвалесцентов, внесено не было. Для пациентов с нетяжелым течением COVID-19, затронутых наивысшим риском госпитализации Практические сведения Режим дозирования и способ введения. В исследованиях с участием пациентов с нетяжелым течением COVID-19 комбинированный препарат на основе моноклональных антител применяли внутривенно в различных дозах с диапазоном общей дозы от 1200 мг до 8000 мг (от 600 мг до 4000 мг каждого антитела), при этом препарат продемонстрировал свою эффективность при всех режимах дозирования, включая самую низкую дозу, составившую 1200 мг общей дозы препарата (по 600 мг каждого антитела). В условиях ограниченного доступа и недостаточности ресурсов системам здравоохранения придется принимать решения в отношении того, какую дозу комбинации казиривимаба и имдевимаба и какой способ введения препарата (внутривенный или подкожный) они будут использовать. В подразделе, посвященном вопросам приемлемости и практической осуществимости (раздел «Фактические сведения, лежащие в основе данной рекомендации»), изложен ряд соображений в помощь при выборе общей дозы препарата в возможном диапазоне от 1200 мг до 2400 мг. Наблюдение. Хотя в имеющихся исследованиях не было получено убедительных доказательств того, что применение комбинации казиривимаба и имдевимаба вызывает аллергические реакции, такую возможность исключить нельзя. Препарат вводится путем внутривенной инфузии с использованием встроенного или присоединяемого к инфузионной системе стерильного фильтра с диаметром пор 0,2 мкм. После введения препарата пациенты должны находиться под медицинским наблюдением на предмет выявления признаков тяжелой анафилаксии. Условная рекомендация в пользу применения Обновлено Авторы рекомендуют назначение комбинации казиривимаба и имдевимаба в том случае, если имеются возможности вирусного генотипирования для подтверждения заражения чувствительным вариантом вируса SARS-CoV-2 (то есть за исключением варианта «омикрон» ВА.1) (условная рекомендация в пользу применения). • Информация для содействия выявлению пациентов, затронутых наивысшим риском госпитализации, содержится в разделе 6.1. • Доступен ряд вариантов лечения: см. инструмент содействия принятию решений, в котором представлены сведения о пользе и вреде применения комбинации нирматрелвира и ритонавира, молнупиравира, ремдесивира и моноклональных антител, в том числе сотровимаба и комбинации казиривимаба и имдевимаба. • Группа по разработке руководящих принципов пришла к выводу о том, что комбинация нирматрелвира и ритонавира является наилучшим вариантом лечения, так как данные средства, вероятно, обладают большей эффективностью в отношении профилактики госпитализации по сравнению с альтернативами, обладают меньшим количеством эффектов, вызывающих обеспокоенность, по сравнению с молнупиравиром и более удобны при приеме по сравнению с ремдесивиром или антителами, требующими внутривенного введения. 79 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Назначение комбинации казиривимаба и имдевимаба пациентам с нетяжелым течением заболевания, вероятно, позволяет снизить риск госпитализации и продолжительность проявления симптоматики. Маловероятно, что введение комбинации казиривимаба и имдевимаба может приводить к развитию серьезных побочных явлений, в частности аллергических реакций. Убедительность фактических данных Группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных ввиду их косвенного характера, обусловленного главным образом ограниченной доступностью разработанного эмпирическим путем метода прогнозирования риска, позволяющего определять риск госпитализации у отдельных пациентов (31). Кроме того, эксперты группы посчитали, что возможность появления новых вариантов вируса, против которых терапия, возможно, будет менее эффективна, также играет определенную роль в косвенности данных. Таким образом, группа по разработке руководящих принципов понизила оценку степени убедительности фактических данных в отношении риска госпитализации и продолжительности проявления симптоматики до средней. Кроме того, группа понизила оценку степени убедительности фактических данных в отношении аллергических реакций до средней степени ввиду неоднозначности трактовки данных, но посчитала, что отсутствие сообщений о серьезных побочных явлениях в ходе наблюдений служит доказательством высокой степени убедительности данных. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что почти все надлежащим образом информированные пациенты, чей риск госпитализации, как правило, является низким, будут склонны отказаться от применения комбинации казиривимаба и имдевимаба, и только пациенты из группы высокого риска (т.е. невакцинированные, пожилые, а также лица с иммунодефицитными состояниями) предпочтут получить данное лечение. Ресурсная оснащенность и другие аспекты Приемлемость и практическая осуществимость Группа отметила низкую вероятность того, что лечение комбинацией казиривимаба и имдевимаба будет доступно всем лицам, которые, при наличии такой возможности, предпочли бы получить указанное лекарственное средство. Это положение еще раз подтверждает вынесенную рекомендацию, предписывающую назначать комбинацию казиривимаба и имдевимаба только пациентам с наиболее высоким риском госпитализации. К основным трудностям практического осуществления относятся ограниченные объемы производства комбинации казиривимаба и имдевимаба, а также, применительно к амбулаторным пациентам, необходимость внутривенного введения. Вероятно, что в связи с данным требованием введение антител должно будет осуществляться в специализированных медицинских учреждениях, располагающих достаточным количеством препарата и персоналом, способным обеспечить безопасное и эффективное применение данного лечебного вмешательства. Таким образом, для того чтобы рассматриваемое вмешательство получило широкое применение, системы здравоохранения должны будут решить перечисленные проблемы. Выбор дозировки. Так как в различных исследованиях использовались разные дозы комбинированного препарата на основе моноклональных антител, системам здравоохранения будет необходимо выбрать один из допустимых режимов дозирования, что можно сделать исходя из ценностных ориентиров и предпочтений. В случае, если приоритетной задачей является обеспечение конкретным средством лечения как можно большего количества лиц, целесообразно использовать самую низкую эффективную дозу, применявшуюся в исследованиях с участием пациентов с нетяжелой формой заболевания, то есть в общей дозе 1200 мг (по 600 мг каждого вида антител) (103). Если же приоритетной задачей является обеспечение эффективности лечения у каждого пациента, которому был назначен данный препарат, а также минимизация риска возникновения резистентности, можно использовать более высокую общую дозу для внутривенного введения, составляющую 2400 мг (по 1200 мг каждого антитела). Путь введения. Аналогичные соображения в отношении ценностных ориентиров и предпочтений возникают и при выборе между внутривенным введением, которое использовалось в четырех исследованиях, включенных в ОДСМА (в рамках общего адаптивного рандомизированного мастер-протокола клинических исследований) (104), и подкожным введением, использовавшимся в исследовании, в ходе которого препарат вводили с профилактической целью (105). При внутривенном введении максимальная концентрация препарата достигается быстрее, чем при подкожном; однако и в том, и в другом случае экспозиция будет выше прогнозируемого порогового уровня терапевтического воздействия. В случае если приоритетной задачей является обеспечение максимальной эффективности лечения у каждого пациента, которому был назначен препарат, следует предпочесть внутривенное введение. В случае если приоритетная задача состоит в том, чтобы с учетом практических трудностей, обусловленных необходимостью организации внутривенного введения препарата широкому кругу амбулаторных пациентов, обеспечить как можно большему числу пациентов возможность получения пользы от данного средства лечения, целесообразно обеспечить доступность подкожного введения. При подкожном введении допустимо вводить только самую низкую общую дозу препарата, которая составляет 1200 мг (по 600 мг каждого вида антител). 80 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Обоснование Рассмотренные в совокупности фактические данные, ценностные ориентиры и предпочтения, а также вопросы практического осуществления легли в основу условной рекомендации использовать комбинацию казиривимаба и имдевимаба только у пациентов с нетяжелым течением COVID-19, подвергающихся наиболее высокому риску госпитализации. Несмотря на наличие фактических данных средней степени убедительности, указывающих на существенное снижение относительного риска госпитализации, вероятно, что лишь меньшинство пациентов, относящихся к группе наиболее высокого риска, получат значимую пользу от применения данного вмешательства. В рамках оказания стандартного объема помощи пациентам с нетяжелым течением COVID-19 не имеется инструментов для надежного выявления лиц с наиболее высоким риском госпитализации. Сложность указанной клинической задачи в сочетании с ограниченной доступностью препарата и необходимостью парентерального введения для группы пациентов, обычно получающих лечение по месту жительства, создают ряд проблем в оказании помощи, которые предстоит решить системам здравоохранения. Возможность применения Так как во всех рассмотренных РКИ участвовали взрослые, применимость данной рекомендации к детям остается невыясненной. Вместе с тем группа по разработке руководящих принципов не имела оснований предполагать, что ответ на лечение комбинацией казиривимаба и имдевимаба у детей будет отличаться. С другой стороны, риск госпитализации у детей, как правило, крайне низок, и группа по разработке руководящих принципов пришла к выводу о том, что при отсутствии иммуносупрессии или другого значимого фактора риска детям не следует проводить данное вмешательство. Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: комбинация казиривимаба и имдевимаба Сравнение: стандарт оказания помощи Резюме Резюме фактических данных Резюме фактических данных в отношении пациентов с нетяжелым течением COVID-19 было составлено на основе ОДСМА (2), в которых были объединены результаты четырех РКИ с участием 4722 пациентов, рандомизированных в группу лечения комбинацией казиривимаба и имдевимаба либо в группу стандартного лечения (104). На момент рассмотрения данных группа по разработке руководящих принципов все исследования были зарегистрированы и доступны в форме предварительной публикации. Описание клинических испытаний представлено в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения комбинации казиривимаба и имдевимаба для лечения пациентов с нетяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. Особые соображения, касающиеся оценки риска в исходный момент времени, на основании которой рассчитывается величина абсолютного эффекта Применительно к риску госпитализации – основному конечному результату, послужившему основанием для вынесения рекомендации в пользу применения комбинации казиривимаба и имдевимаба, – экспертная группа использовала показатель исходного риска, равный 4,2% (42 случая на 1000 пациентов), исходя из медианного значения данного показателя в контрольной группе четырех РКИ, данные которых включались в анализ. Для того чтобы увеличить статистическую мощность исследования при выявлении возможных эффектов лечения, в указанные клинические испытания были набраны пациенты с повышенным риском госпитализации. Таким образом, исходный риск госпитализации в этих исследованиях был заметно выше, чем для большинства пациентов с нетяжелой формой COVID-19. Анализ в подгруппах Группой по разработке руководящих принципов не было найдено убедительных данных, подтверждающих наличие эффектов в подгруппах пациентов с нетяжелым течением COVID-19, выделенных по критерию возраста пациента или времени от момента начала заболевания. 81 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Комбинация казиривимаба и имдевимаба Убедительность фактических данных (качество Резюме в текстовом формате Смертность Отношение шансов: 0,57 (95% ДИ: 0,26–1,2) Данные по 4722 пациентам, полученные в 4 исследованиях (рандомизированные контролируемые) 6 на 1000: 3 на 1000) Средняя Ввиду крайне косвенного характера данных1 Применение комбинации казиривимаба и имдевимаба не оказывает значимого влияния на уровень смертности. Разница: сокращение на 3 случая на 1000 (ДИ 95%: сокращение на 4 случая – увеличение на 1 случай) Искусственная вентиляция легких Отношение шансов: 0,22 (95% ДИ: 0,03–1,21) Данные по 3432 пациентам, полученные в 2 исследованиях (рандомизированные контролируемые) 8 на 1000 2 на 1000 Средняя Ввиду крайне косвенного характера данных2 Применение комбинации казиривимаба и имдевимаба, вероятно, не оказывает значимого влияния на потребность в искусственной вентиляции легких. Разница: сокращение на 6 случаев на 1000 (95% ДИ: сокращение на 8 случаев – увеличение на 2 случая) Госпитализация Риск в исследованиях Отношение шансов: 0,29 (95% ДИ: 0,17–0,48) На основании данных по 4722 пациентам в 4 исследовании (рандомизированные контролируемые) 35 на 1000 10 на 1000 Средняя Ввиду крайне косвенного характера данных3 Применение комбинации казиривимаба и имдевимаба предположительно приводит к снижению риска госпитализации. Разница: сокращение на 25 случаев на 1000 (95% ДИ: сокращение на 29 случаев – сокращение на 18 случаев) Госпитализация Группа крайне высокого риска Отношение шансов: 0,29 (95% ДИ: 0,17–0,48) На основании данных по 4722 пациентам в 4 исследованиях (рандомизированные контролируемые) 60 на 1000 18 на 1000 Средняя Ввиду крайне косвенного характера данных4 Применение комбинации казиривимаба и имдевимаба предположительно приводит к снижению риска госпитализации. Разница: сокращение на 42 случая на 1000 (95% ДИ: сокращение на 49 случаев – сокращение на 30 случаев) Госпитализация Группа наивысшего риска Отношение шансов: 0,29 (95% ДИ: 0,17–0,48) На основании данных по 4722 пациентам в 4 исследованиях (рандомизированные контролируемые) 100 на 1000 31 на 1000 Средняя Ввиду крайне косвенного характера данных5 Применение комбинации казиривимаба и имдевимаба предположительно приводит к снижению риска госпитализации. Разница: сокращение на 69 случаев на 1000 (95% ДИ: сокращение на 81 случай – сокращение на 49 случаев) Нежелательные явления, приводящие к отмене препарата На основании данных по 5284 пациентам в 4 исследованиях (рандомизированные контролируемые) 0 на 1000 95% ДИ Высокая Применение комбинации казиривимаба и имдевимаба не вызывает значимого повышения частоты развития нежелательных явлений, приводящих к отмене препарата. Разница: снижение на 8 на 1000 (95% ДИ) 82 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Комбинация казиривимаба и имдевимаба Убедительность фактических данных (качество Резюме в текстовом формате Аллергические реакции Данные по 15 406 участникам, полученные в 4 исследованиях (рандомизированные контролируемые) 3 на 1000 9 на 1000 Средняя Ввиду крайней неоднозначности трактовки данных6 Применение комбинации казиривимаба и имдевимаба предположительно не приводит к существенному повышению частоты аллергических реакций. Разница: увеличение на 6 случаев на 1000 (ДИ 95% сокращение на 1 случай – увеличение на 29 случаев) Время до исчезновения симптомов Предпочтителен более низкий уровень На основании данных по: 3084 участникам в 2 исследованиях (рандомизированные контролируемые) 9 (среднее значение) 4,9 (среднее значение) Средняя Ввиду крайне косвенного характера данных7 Применение комбинации казиривимаба и имдевимаба предположительно приводит к более быстрому клиническому улучшению. Разница: СР на 4,1 меньше (95% ДИ: меньше на 5,7 дня – меньше на 1,8 дня) Продолжительность госпитализации (не в стационаре в исходный момент времени) Предпочтителен более низкий уровень На основании данных по: 111 участникам в 2 исследованиях (рандомизированные контролируемые) 9,6 (среднее значение) 8,2 (среднее значение) Низкая Ввиду крайней неоднозначности трактовки данных8 Применение комбинации казиривимаба и имдевимаба может не оказывать значимого влияния на продолжительность госпитализации. Разница: СО: на 1,4 меньше (95% ДИ: на 4,6 дня меньше – на 1,8 дня больше) 1. Косвенный характер данных: существенный. Имеется существенный разброс в показателях исходного риска летального исхода между пациентами. Применение комбинации казиривимаба и имдевимаба может принести значительную пользу пациентам с крайне высоким риском летального исхода. 2. Косвенный характер данных: существенный. Имеется существенный разброс в показателях исходного риска потребности в искусственной вентиляции легких между пациентами. Применение комбинации казиривимаба и имдевимаба может принести значительную пользу пациентам с крайне высоким риском потребности в искусственной вентиляции легких. 3. Косвенный характер данных: существенный. Различия между популяцией, представляющей интерес для исследователей, и изученными популяциями: преобладающие штаммы вируса, циркулирующие в настоящее время, не совпадают с теми, которые циркулировали во время проведения исследований. 4. Косвенный характер данных: существенный. Различия между популяцией, представляющей интерес для исследователей, и изученными популяциями: преобладающие штаммы вируса, циркулирующие в настоящее время, не совпадают с теми, которые циркулировали во время проведения исследований. 5. Косвенный характер данных: существенный. Различия между популяцией, представляющей интерес для исследователей, и изученными популяциями: преобладающие штаммы вируса, циркулирующие в настоящее время, не совпадают с теми, которые циркулировали во время проведения исследований. 6. Неоднозначность трактовки данных: существенная. 7. Косвенный характер данных: существенный. Различия между популяцией, представляющей интерес для исследователей, и изученными популяциями: преобладающие штаммы вируса, циркулирующие в настоящее время, не совпадают с теми, которые циркулировали во время проведения исследований. 8. Неоднозначность трактовки данных: крайняя. 83 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Режим дозирования и способ введения. В исследовании RECOVERY, в котором участвовали пациенты с тяжелым и крайне тяжелым течением COVID-19, комбинированный препарат на основе рассматриваемых моноклональных антител вводили внутривенно в общей дозе, равной 8000 мг (по 4000 мг каждого антитела), тогда как в четырех исследованиях с участием пациентов с нетяжелой формой заболевания (в рамках общего адаптивного рандомизированного основного протокола клинических исследований) общая доза препарата, также вводимого внутривенно, различалась и составляла от 1200 мг до 8000 мг. В условиях ограниченного доступа, а также с учетом ресурсных соображений, перед системами здравоохранения встанет выбор дозировок комбинированного препарата казиривимаба и имдевимаба. В подразделе, посвященном вопросам приемлемости и практической осуществимости (раздел «Фактические сведения, лежащие в основе данной рекомендации»), представлен ряд соображений в помощь при выборе общей дозы препарата в возможном диапазоне от 2400 мг до 8000 мг. Диагностическое тестирование. Задача по выявлению лиц с серонегативным статусом среди пациентов с клиническими проявлениями тяжелого или крайне тяжелого течения COVID-19 требует использования серологических экспресс-тестов с адекватными диагностическими характеристиками. Системам здравоохранения необходимо будет внедрить такие тесты, как указано в разделе, посвященном вопросам приемлемости и практической осуществимости. Наблюдение. Хотя в имеющихся исследованиях не было получено убедительных доказательств того, что применение комбинации казиривимаба и имдевимаба вызывает аллергические реакции, такую возможность исключить нельзя. Препарат вводится путем внутривенной инфузии с использованием встроенного или присоединяемого к инфузионной системе стерильного фильтра с диаметром пор 0,2 мкм. После введения препарата пациенты должны находиться под медицинским наблюдением на предмет выявления признаков аллергических реакций. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Применение комбинации казиривимаба и имдевимаба в общей популяции пациентов с тяжелым и крайне тяжелым течением COVID-19 может не оказывать влияния на уровень смертности, а их влияние на снижение потребности в искусственной вентиляции легких и сокращение сроков госпитализации остается крайне неопределенным. С другой стороны, достоверность эффектов, наблюдаемых в подгруппах, свидетельствует о том, что применение комбинации казиривимаба и имдевимаба предположительно снижает показатели смертности у серонегативных пациентов, при этом величина абсолютного эффекта находится в диапазоне от сокращения числа случаев смерти на 39 случаев на 1000 пациентов (95% ДИ: в диапазоне от сокращения на 62 случая до сокращения на 13 случаев) при тяжелом течении заболевания до сокращения на 69 случаев на 1000 пациентов (95% ДИ: в диапазоне от сокращения на 110 случаев до сокращения на 23 случая) при крайне тяжелом течении. У серонегативных пациентов данное вмешательство предположительно снижает потребность в искусственной вентиляции легких (величина абсолютного эффекта: сокращение числа случаев перевода на искусственную вентиляцию легких на 42 случая на 1000 пациентов; 95% ДИ: в диапазоне от сокращения на 74 случая до сокращения на 6 случаев). За исключением достоверных эффектов, наблюдаемых в подгруппах при анализе по критерию серологического статуса, экспертной группой не было найдено убедительных данных, подтверждающих наличие эффектов в подгруппах пациентов с нетяжелым течением заболевания, которые были выделены на основании возраста или времени от момента начала заболевания, а также в подгруппах пациентов с тяжелым и крайне тяжелым течением заболевания, выделенных на основании возраста, времени от момента начала заболевания и степени тяжести заболевания. Убедительность фактических данных Данные по влиянию комбинации казиривимаба и имдевимаба на показатели смертности в группе пациентов с тяжелым и крайне тяжелым течением COVID-19 имели низкую степень убедительности в связи с неоднозначностью трактовки данных и высокой вероятностью наличия существенных различий в эффекте применения данного вмешательства у серопозитивных и у серонегативных пациентов, включенных в общую группу исследования. С учетом дополнительного риска систематической ошибки данные о влиянии вмешательства на потребность в искусственной вентиляции легких и Условная рекомендация в пользу применения Обновлено Авторы рекомендуют назначение комбинации казиривимаба и имдевимаба пациентам с серонегативным статусом и при наличии возможности вирусного генотипирования для подтверждения заражения чувствительным вариантом вируса SARS-CoV-2 (то есть за исключением варианта «омикрон» ВА.1) (условная рекомендация в пользу применения). • Так как преимущества применения комбинации казиривимаба и имдевимаба наблюдались только у серонегативных пациентов, для надлежащего применения этой рекомендации врачам необходимо выявлять таких пациентов с помощью надежных тестов, доступных в месте оказания медицинской помощи (см. раздел, посвященный фактическим сведениям, лежащим в основе данного решения). • Лечение комбинацией казиривимаба и имдевимаба проводится в дополнение к применяемому стандарту оказания помощи, который включает кортикостероиды и блокаторы рецепторов к IL-6. 84 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) продолжительность госпитализации в указанной группе пациентов характеризовались крайне низкой степенью убедительности. Степень убедительности фактических данных, касающихся влияния на показатели смертности в группе серонегативных пациентов с тяжелым и крайне тяжелым течением COVID-19, была оценена как средняя в связи с неоднозначностью трактовки данных (доверительный интервал накрывает такие небольшие величины эффекта, как 14 случаев на 1000, что некоторыми пациентами может восприниматься как несущественное сокращение случаев смерти) и косвенного характера данных (нельзя исключить появление вариантов вируса, против которых эффективность комбинированного препарата антител казиривимаба и имдевимаба будет ниже). Применительно к оценке влияния на потребность в искусственной вентиляции легких группа отметила дополнительный риск систематической ошибки, которая могла иметь место на фоне отсутствия маскировки данных, в связи с чем была установлена низкая степень убедительности фактических данных. Кроме того, группа выявила крайнюю неоднозначность трактовки данных, касающихся влияния на продолжительность госпитализации, в связи с чем данным была присвоена очень низкая степень убедительности. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) члены группы по разработке руководящих принципов пришли к выводу о том, что большинство либо все надлежащим образом информированные пациенты с тяжелым и крайне тяжелым течением COVID-19, чей серологический статус является негативным, предпочтут получить лечение комбинацией казиривимаба и имдевимаба. Другие пациенты – с позитивным или неизвестным серологическим статусом – вероятно, будут склонны отказаться от данного вмешательства. Группа по разработке руководящих принципов в первую очередь рассматривала проблему с точки зрения отдельного пациента, однако наряду с этим были учтены важные с точки зрения популяции аспекты: практическая осуществимость, приемлемость, равноправный доступ и ценовые соображения. В данном случае соображения практической осуществимости сыграли важную роль в вынесении рекомендации условного характера. Применительно к пациентам с тяжелой и крайне тяжелой формами заболевания существенные трудности создает как ограниченная доступность терапевтических средств, так и необходимость при определении тактики лечения проводить серологическое тестирование в целях выявления серонегативных пациентов. Ресурсная оснащенность и другие аспекты Стоимость и доступность С учетом высокой стоимости и ограниченной доступности комбинации казиривимаба и имдевимаба, а также трудностей, связанных с проведением серологического тестирования, препятствия для обеспечения доступа к этому препарату в странах с низким и средним уровнем дохода могут оказаться труднопреодолимыми. Таким образом, рекомендация экспертной группы применять данное вмешательство только у серонегативных пациентов может обострить неравенство в области здравоохранения. С другой стороны, принимая во внимание доказанные преимущества для пациентов, она должна обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этому средству лечения. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. Приемлемость и практическая осуществимость Поставки комбинированного препарата казиривимаба и имдевимаба, вероятно, будут выполняться в ограниченном объеме, что приведет к проблемам с доступностью препарата и, возможно, вызовет необходимость нормировать его назначение. Кроме того, для обеспечения преимуществ данного вида лечения у пациентов с признаками тяжелого или крайне тяжелого течения COVID-19 потребуется определять серологический статус пациентов. Поэтому при внедрении данного вмешательства системам здравоохранения необходимо учитывать такие важнейшие факторы, как обеспечение доступности точных серологических экспресс-тестов, а также режим дозирования и способ введения препарата, которые они собираются использовать. Серологические экспресс-тесты. В настоящее время имеются в наличии доступные по цене тест-системы, диагностические характеристики которых аналогичны характеристикам референтного метода диагностики, использовавшегося для выявления серонегативных пациентов в исследовании RECOVERY, а именно оксфордской тест- системы для проведения флуоресцентного иммуноферментного твердофазного анализа ELISA на сывороточные антитела класса IgG к спайк-белку SARS-CoV-2, с произвольным пороговым значением чувствительности, определяемым на основе панели положительных контрольных образцов. С указанной диагностической целью можно применять и некоторые тест- системы на основе латерального проточного иммуноанализа, которые позволяют получить результат за несколько минут (106)(107)(108). Вместе с тем системы здравоохранения должны привлечь к отбору и внедрению экспресс-теста или тест- системы специалистов, обладающих экспертными знаниями в данной предметной области, чтобы с их помощью выбрать те средства диагностики, которые наиболее применимы к их условиям. Выбор дозировки. В клиническом исследовании с участием пациентов с тяжелым и крайне тяжелым течением заболевания (RECOVERY) комбинацию казиривимаба и имдевимаба применяли в общей дозе 8000 мг (по 4000 мг каждого антитела); в клинических исследованиях, включавших пациентов с нетяжелой формой заболевания, использовались общие дозы в диапазоне от 1200 мг до 8000 мг (по 600 мг–4000 мг каждого антитела), при этом в обоих случаях был достигнут сходный эффект в отношении снижения потребности в госпитализации. В исследовании с участием пациентов с нетяжелым течением COVID-19 были определены фармакокинетические профили казиривимаба и имдевимаба, применяемых в общих дозах от 1200 мг до 8000 мг (по 600 мг–4000 мг каждого моноклонального антитела) (104). Согласно полученным результатам, при введении препарата антител происходит быстрое достижение их целевых терапевтических концентраций в сыворотке крови, которые поддерживаются на данном уровне в течение 28 дней даже при использовании самой низкой общей дозы препарата, составляющей 1200 мг (по 600 мг каждого антитела), хотя вместе с тем было отмечено значительное различие сывороточных концентраций препарата у разных пациентов. Поэтому можно сделать вывод о том, что использование доз ниже, чем те, которые применялись в исследовании RECOVERY (общая доза 8000 мг) для лечения 85 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) пациентов с тяжелым и крайне тяжелым течением заболевания, может принести такую же пользу. С другой стороны, существует теоретическая, хотя и не проверенная опытными данными возможность того, что фармакокинетические различия, наблюдаемые у пациентов с тяжелым и крайне тяжелым течением по сравнению с пациентами, имеющими нетяжелую форму заболевания, могут привести к снижению экспозиции препарата (см. раздел «Механизм действия»). В таком случае вероятно повышение риска недостаточного терапевтического воздействия препарата у некоторых пациентов, что, в свою очередь, может увеличить риск неэффективности лечения и формирования вирусной резистентности. В отсутствие клинических данных об эффективности лечения пациентов с тяжелым и крайне тяжелым течением заболевания при использовании доз ниже 8000 мг выбор дозы может определяться ценностными ориентирами и предпочтениями. Если приоритетной задачей является обеспечение эффективности лечения у каждого пациента, которому был назначен данный препарат, а также минимизация риска возникновения резистентности, можно использовать общую дозу для внутривенного введения, равную 8000 мг (по 4000 мг каждого антитела). Если же приоритетная задача состоит в том, чтобы с учетом ограниченной доступности и высокой стоимости препарата обеспечить как можно большему числу лиц возможность получить пользу от данного средства лечения, целесообразнее будет использовать более низкую общую дозу для внутривенного введения, равную 2400 мг (по 1200 мг каждого антитела). В период дефицита лекарственных средств может быть необходима приоритизация использования комбинации казиривимаба и имдевимаба по механизму клинической сортировки. Сортировка может осуществляться по принципу приоритизации пациентов, затронутых наивысшим риском смертности в исходный момент времени (например, лица с крайне тяжелым течением инфекции по сравнению с лицами с тяжелым течением), для которых абсолютная польза данного лечения является наибольшей. Например, несмотря на постоянные относительные эффекты (ОШ для показателя смертности 0,85) комбинации казиривимаба и имдевимаба у серонегативных пациентов, у пациентов в крайне тяжелом состоянии снижение абсолютного риска смертности составит 69 случаев на 1000 (95% ДИ: сокращение на 110–23 случая), тогда как у пациентов в тяжелом состоянии составит 39 случаев на 1000 (95% ДИ: сокращение на 62–13 случаев). Другие предложения, касающиеся приоритизации, однако непосредственно не обоснованные фактическими данными, включают закрепление приоритета за пациентами с активно ухудшающейся динамикой заболевания и отказ от терапии комбинацией казиривимаба и имдевимаба у лиц с установленной полиорганной недостаточностью (для которых преимущества, по-видимому, будут ниже). Обоснование В случае пациентов с тяжелым или крайне тяжелым течением заболевания условная рекомендация в пользу применения комбинации казиривимаба и имдевимаба отражает вероятность того, что любые преимущества данного вида лечения будут наблюдаться только у серонегативных пациентов. В исследовании RECOVERY, которое послужило источником всех фактических данных по пациентам с тяжелым и крайне тяжелым течением заболевания, серологический статус пациентов на исходном уровне оценивался в заранее запланированном, но ретроспективном анализе с использованием лабораторного исследования на антитела к спайк-белку вируса. Для того чтобы использовать результаты исследования в клинической практике, необходимо интегрировать оценку серологического статуса в процесс принятия клинических решений, предшествующий назначению лечения. Это подразумевает, что для определения показаний к назначению препарата в данной группе пациентов необходимо обеспечить быстрое установление серологического статуса пациента на момент появления признаков тяжелой или крайне тяжелой формы заболевания. В настоящее время на рынке имеется целый ряд относительно недорогих экспресс-тестов с адекватными диагностическими характеристиками, которые следует шире использовать в медицинских учреждениях, располагающих возможностью назначения пациентам из этой группы комбинации казиривимаба и имдевимаба. Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. К счастью, у детей, заболевших COVID-19, инфекция практически никогда не протекает в крайне тяжелой форме. Если болезнь все же приобретает крайне тяжелое течение, и при этом ребенок имеет негативный серологический статус, возможно, что применение комбинации казиривимаба и имдевимаба у этой категории детей принесет пользу. Отсутствие соответствующих сведений не позволило группе по разработке руководящих принципов разработать конкретные рекомендации для других особых групп населения, таких как беременные женщины. Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 и серонегативным статусом Вмешательство: комбинация казиривимаба и имдевимаба Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных использовались ОДСМА результатов одного крупного исследования (RECOVERY) с участием 9785 пациентов с тяжелым или крайне тяжелым течением COVID-19, большинство из которых получали кортикостероиды (109). На момент рассмотрения данных группой по разработке руководящих принципов это исследование было зарегистрировано и доступно в форме предварительной публикации. Описание клинических испытаний представлено в таблице. 86 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения комбинации казиривимаба и имдевимаба для лечения серонегативных пациентов с тяжелым и крайне тяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. Особые соображения, касающиеся оценки риска в исходный момент времени, на основании которой рассчитывается величина абсолютного эффекта Для оценки важного показателя смертности в группе пациентов с тяжелым и крайне тяжелым течением COVID‑19 был взят оценочный показатель исходного риска наступления летального исхода, равный 13% (130 случаев на 1000 пациентов). Как и в отношении других соответствующих рекомендаций, представленных в данном документе, величина исходного риска смертности заимствована из исследования SOLIDARITY для пациентов с тяжелой и крайне тяжелой формами COVID-19 с внесением поправки на лечебный эффект применения кортикостероидов. По мнению членов группы по разработке руководящих принципов, оптимальным источником фактических данных для оценки исходного риска смертности в группе серонегативных пациентов является контрольная группа исследования RECOVERY. Риск летального исхода у серонегативных пациентов как с тяжелым (26%; 260 случаев на 1000 пациентов), так и с крайне тяжелым (46%; 460 случаев на 1000 пациентов) течением заболевания был значительно выше, чем в общей популяции. Таким образом, серонегативные пациенты представляют собой группу очень высокого риска, что объясняет существенное снижение абсолютного риска смертности в этой группе (3,9% при тяжелой форме и 6,9% при крайне тяжелой форме заболевания), несмотря на умеренное снижение относительного риска на 15%. Анализ в подгруппах Высокая достоверность эффектов, наблюдаемых в подгруппах, позволила заключить, что применение комбинации казиривимаба и имдевимаба, по-видимому, позволяет снизить уровень смертности у серонегативных пациентов, но не у серопозитивных пациентов. Степень достоверности эффекта, наблюдаемого в подгруппах, оценивалась с использованием инструмента ICEMAN (110). В пользу достоверности эффекта, выявленного в подгруппах, свидетельствовали следующие важные факторы: наличие у исследователей априорной гипотезы в отношении направления эффекта в подгруппах; небольшое количество таких гипотез; фактические данные, основанные на сравнении подгрупп пациентов в каждом исследовании; предположение о существовании схожего эффекта в подгруппах в отношении потребности в искусственной вентиляции легких; значение р при проверке взаимодействия между переменными, составившее 0,001. На рисунке 2 изображена лесовидная диаграмма, на которой представлены точечная оценка и доверительный интервал показателя влияния изучаемого вмешательства на смертность среди серопозитивных и серонегативных пациентов, свидетельствующие о пользе применения вмешательства в группе серонегативных пациентов и отрицательном эффекте изучаемого средства терапии у серопозитивных пациентов, и отсутствие перекрытия доверительных интервалов, что соответствует значению p=0,001, определенному в тесте взаимодействия (109). Рисунок 2. Показатели смертности у серопозитивных и серонегативных пациентов с тяжелым и крайне тяжелым течением COVID-19 ДИ – доверительный интервал, ОР – относительный риск. Данные очень низкой степени убедительности указывают на возможность сокращения сроков госпитализации у серонегативных пациентов. Помимо зарегистрированных эффектов в подгруппах, выделенных по критерию серологического статуса, экспертной группой не было найдено убедительных данных, подтверждающих наличие эффекта в подгруппах пациентов различного возраста, с различной продолжительностью периода от начала заболевания или с различной тяжестью заболевания (при сравнении пациентов с тяжелым и крайне тяжелым течением болезни). 87 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Отсутствие лечения комбинацией казиривимаба и имдевимаба Вмешательство Комбинация казиривимаба и имдевимаба Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Тяжелое течение заболевания относительный риск: 0,85 (95% ДИ: 0,76–0,95) Данные по 2823 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 260 на 1000 221 на 1000 Средняя В связи с косвенным характером данных и неоднозначностью их трактовки1 Применение комбинации казиривимаба и имдевимаба предположительно приводит к снижению уровня смертности. Разница: сокращение на 39 случаев на 1000 (95% ДИ: сокращение на 62 случая – сокращение на 13 случаев) Смертность Крайне тяжелое течение относительный риск: 0,85 (95% ДИ: 0,76–0,95) Данные по 2823 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 460 на 1000 391 на 1000 Средняя В связи с косвенным характером данных и неоднозначностью их трактовки2 Применение комбинации казиривимаба и имдевимаба предположительно приводит к снижению уровня смертности. Разница: сокращение на 69 случаев на 1000 (95% ДИ: сокращение на 110 случаев – сокращение на 23 случая) Искусственная вентиляция легких Относительный риск 0,87 (95% ДИ: 0,77–0,98) Данные по 2410 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 320 на 1000) 278 на 1000 Низкая В связи с риском систематической ошибки, косвенным характером данных и неоднозначностью их трактовки3 Применение комбинации казиривимаба и имдевимаба, вероятно, приводит к снижению потребности в искусственной вентиляции легких. Разница: сокращение на 42 случая на 1000 (95% ДИ: сокращение на 74 случая – сокращение на 6 случаев) Продолжительность госпитализации На основании данных по: 3153 участникам в 1 исследовании (рандомизированные контролируемые) Медиана продолжительности пребывания в стационаре на фоне применения комбинации казиривимаба и имдевимаба сократилась на 4 дня (13 дней по сравнению с 17 днями). Крайне низкая В связи с высокой вероятностью систематической ошибки и крайней неоднозначностью трактовки данных4 Влияние на сокращение сроков госпитализации остается крайне неопределенным. 1. Неоднозначность трактовки данных: существенная. Единственное исследование. 2. Неоднозначность трактовки данных: существенная. Единственное исследование. 3. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: существенная. 4. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. Клиническая проблема/вопрос PICO Популяция: Пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: комбинация казиривимаба и имдевимаба Сравнение: стандарт оказания помощи Резюме Резюме фактических данных Резюме фактических данных было основано на СМА результатов одного крупного исследования (RECOVERY) с участием 9785 пациентов с тяжелым или крайне тяжелым течением COVID-19, большинство из которых получали кортикостероиды (109). На момент рассмотрения данных группой по разработке руководящих принципов это исследование было зарегистрировано и доступно в форме предварительной публикации. Описание клинических испытаний представлено в таблице. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения комбинации казиривимаба и имдевимаба для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. 88 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Комбинация казиривимаба и имдевимаба Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Крайне тяжелое или тяжелое течение заболевания Отношение шансов: 0,94 (95% ДИ: 0,86–1,03) Данные по 9785 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 130 на 1000 122 на 1000 Низкая Ввиду крайне косвенного характера данных и неоднозначности их трактовки1 Применение комбинации казиривимаба и имдевимаба, вероятно, не оказывает значимого влияния на уровень смертности. Разница: сокращение на 8 случаев на 1000 (95% ДИ: сокращение на 18 случаев – увеличение на 4 случая) Искусственная вентиляция легких Отношение шансов: 0,95 (95% ДИ: 0,87–1,04) Данные по 6637 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 86 на 1000 82 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки, косвенным характером данных и неоднозначностью их трактовки2 Влияние на снижение потребности в искусственной вентиляции легких остается крайне неопределенным. Разница: сокращение на 4 случая на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 3 случая) Аллергические реакции Данные по 15 406 пациентам, полученные в 4 исследованиях (рандомизированные контролируемые) 3 на 1000) 9 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Применение комбинации казиривимаба и имдевимаба предположительно не приводит к существенному повышению частоты аллергических реакций. Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 1 случай – увеличение на 29 случаев) Нежелательные явления, приводящие к отмене препарата На основании данных по 5284 пациентам в 4 исследованиях (рандомизированные контролируемые) 2 на 1000) 1 на 1000 Высокая Применение комбинации казиривимаба и имдевимаба не вызывает значимого повышения частоты развития нежелательных явлений, приводящих к отмене препарата. Разница: сокращение на 1 случай на 1000 (95% ДИ: увеличение на 0 случаев – увеличение на 1 случай) Продолжительность госпитализации На основании данных по: 9785 участникам в 1 исследовании (рандомизированные контролируемые) В обеих группах пациентов была одинаковая медиана продолжительности госпитализации (10 дней). Крайне низкая В связи с высокой вероятностью систематической ошибки и крайней неоднозначностью трактовки данных4 Влияние на сокращение сроков госпитализации остается крайне неопределенным. 1. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 2. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 3. Неоднозначность трактовки данных: существенная. 4. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: крайняя. 89 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.10.1. Механизм действия Казиривимаб и имдевимаб представляют собой препараты двух полностью человеческих антител (REGN10933 и REGN10987). Механизм их действия весьма убедителен: они связываются со спайк-белком вируса SARS-CoV-2 (111) и уже доказали свою противовирусную активность в модельных испытаниях на макаках-резусах и переднеазиатских хомяках (112). Данные о фармакокинетике препарата, полученные у пациентов с нетяжелым течением COVID-19, показывают, что внутривенное введение комбинации этих лекарственных средств в общей дозе 1200 мг (по 600 мг каждого антитела) или выше обеспечивает достижение и поддержание противовирусных концентраций обоих антител в течение как минимум 28 дней (42). Кроме того, было установлено, что подкожное введение препарата в общей дозе 1200 мг (по 600 мг каждого антитела), применявшееся в группе неинфицированных лиц с профилактической целью, также позволяет достичь стабильного уровня противовирусных концентраций обоих антител (105). Период полувыведения обоих антител составляет от 25 до 37 дней. В настоящее время отсутствуют сведения о фармакокинетике казиривимаба и имдевимаба у пациентов с тяжелым и крайне тяжелым течением COVID-19, что немаловажно в связи с сообщениями о снижении сывороточной концентрации других моноклональных антител на фоне системной воспалительной реакции организма и корреляции уровня антител с уровнем сывороточной концентрации альбумина и С-реактивного белка (113). Согласно другим опубликованным данным, при комбинированном применении антител они сохраняют свою активность в отношении циркулирующих в настоящее время вариантов вируса, значимых для общественного здравоохранения (114). Хотя механизм действия препарата на основе антител свидетельствует о высокой вероятности его эффективности, было предположено, что он может по-разному действовать на пациентов, в организме которых произошла выработка собственных антител к спайк-белку SARS-CoV-2 (далее – серопозитивные пациенты), и на тех, у которых такие антитела отсутствуют (далее – серонегативные пациенты). Согласно гипотезе, действие препарата может быть более выраженным у серонегативных лиц, еще не сформировавших эффективный гуморальный иммунный ответ, или же проявляться только у этой категории пациентов. Упорядоченный сбор данных с описанием нейтрализации in vitro различных вариантов вируса при помощи моноклональных антител проводится на портале NIH NCATS OpenData (https: /opendata.ncats.nih.gov/variant/activity). В ряде публикаций показано, что нейтрализация в условиях in vitro псевдовируса, содержащего спайк-белок варианта «омикрон» ВА.1, а также нейтрализация в условиях in vitro собственно варианта вируса «омикрон» ВА.1 при помощи казиривимаба или имдевимаба существенно снижается или утрачивается при использовании по отдельности и полностью утрачивается при использовании комбинации этих моноклональных антител. Кроме того, комбинация казиривимаба и имдевимаба не оказывает влияния на субгеномную вирусную РНК в легких или носовых раковинах трансгенных мышей K18 с экспрессией АПФ2 человека, зараженных вариантом вируса «омикрон» BA.1 (https://www.biorxiv.org/content/10.1101/2022.01.23.477397v1.full.pdf+html). Таким образом, доступные в настоящее время доклинические данные не подтверждают эффективности комбинации казиривимаба и имдевимаба в отношении варианта вируса «омикрон» ВА.1. 90 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.11. Блокаторы рецепторов к IL-6 (опубликовано 6 июля 2021 г.) Справочная информация Рекомендации в отношении блокаторов рецепторов к IL-6 (тоцилизумаб или сарилумаб) были опубликованы 6 июля 2021 г. в пятой версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Они были подготовлены в связи с публикацией результатов исследований RECOVERY и REMAP-CAP от февраля 2021 г., а также ввиду поступления в ВОЗ к 1 июня 2021 г. данных нового исследования с участием 1020 пациентов, рандомизированных в группы прямого сравнения тоцилизумаба и сарилумаба в исследовании REMAP-CAP. В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся блокаторов рецепторов к IL-6, внесено не было. ВОЗ вынесла настоятельную рекомендацию в пользу применения ингибиторов JAK, в частности барицитиниба, у пациентов с тяжелым и крайне тяжелым течением COVID-19. Блокаторы рецепторов к IL-6 не следует комбинировать с барицитинибом, и данные препараты необходимо рассматривать как взаимоисключающие. Данные соображения изложены в разделе «Обоснование» для рекомендации, касающейся блокаторов рецепторов к IL-6, и в данной одиннадцатой версии оставлены без изменений. Для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Способ введения. При лечении пациентов с тяжелым или крайне тяжелым течением COVID-19 блокаторы рецепторов к IL–6 вводят внутривенно; подкожное введение в этом случае не используется. Терапия блокаторами рецепторов к IL-6 должна проводиться в сочетании с системными кортикостероидами для перорального либо внутривенного применения с учетом их высокой биодоступности и вместе с тем риска нарушений всасывания при дисфункции кишечника на фоне крайне тяжелого течения инфекции. Продолжительность. Тоцилизумаб или сарилумаб вводят внутривенно в полной дозе, как правило, на протяжении одного часа. Следующая доза может вводиться в период от 12 до 48 часов после первой; в крупных клинических испытаниях данный интервал отличался, так как лечащие врачи выбирали его на собственное усмотрение сообразно выраженности клинического ответа. Продолжительность одномоментно назначаемого курса кортикостероидов обычно составляет до 10 дней, однако может варьировать в диапазоне от 5 до 14 дней. Дозировка. Тоцилизумаб вводят в дозе 8 мг на килограмм фактической массы тела, но не более 800 мг. Сарилумаб, как правило, вводят в дозе 400 мг, аналогично дозировке, которая использовалась в исследовании REMAP-CAP. Коррекция дозы любого из препаратов для пациентов с нарушением функции почек в настоящее время не предусмотрена. Наблюдение. До начала лечения необходимо выполнение стандартного анализа крови с определением количества нейтрофилов, тромбоцитов, уровня трансаминаз и общего билирубина. Необходимо проводить мониторинг всех пациентов на предмет признаков и симптомов инфекции, принимая во внимание повышенный риск ее возникновения на фоне дополнительной к создаваемой системными кортикостероидами иммуносупрессии. Пациенты, получающие продолжительное лечение блокаторами рецепторов к IL-6, затронуты риском активного туберкулезного процесса, инвазивных микозов или оппортунистических инфекций. Необходимо тщательно оценивать риски и пользу данной терапии у пациентов с любой активно протекающей тяжелой инфекцией помимо COVID-19; тоцилизумаб следует применять с осторожностью у пациентов с анамнезом рецидивирующих или хронических инфекций либо с сопутствующими расстройствами здоровья, которые могут предрасполагать к возникновению инфекции. Временные рамки. Терапию блокаторами рецепторов к IL-6 необходимо начинать одновременно с системными кортикостероидами; конкретное время в течение госпитализации или конкретный период заболевания для начала терапии не определен. Вместе с тем в рассмотренных клинических испытаниях терапию блокаторами рецепторов к IL-6 начинали на ранних этапах госпитализации, в связи с чем клиницисты могут рассмотреть возможность применения этого подхода. См. раздел, посвященный ресурсам, равноправию и правам человека. Настоятельная рекомендация в пользу применения Новые сведения Применение блокаторов к IL-6 (тоцилизумаб или сарилумаб) рекомендуется (настоятельная рекомендация в пользу применения). • Ранее была вынесена настоятельная рекомендация применять кортикостероиды у пациентов с тяжелым и крайне тяжелым течением COVID-19 (см. раздел 6.15); в настоящее время у пациентов, отвечающих данным критериям тяжести, рекомендовано применять как кортикостероиды, так и блокаторы рецепторов к IL-6. • В настоящее время ингибитор JAK барицитиниб рекомендуется для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 (см. раздел 6.7). Блокаторы рецепторов к IL-6 не следует комбинировать с барицитинибом, и данные препараты необходимо рассматривать как взаимоисключающие. Выбор в пользу барицитиниба или блокатора рецепторов к IL-6 определяется доступностью соответствующего препарата, а также клиническими и другими обстоятельствами (см. раздел «Обоснование»). 91 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Согласно фактическим данным высокой степени убедительности, применение блокаторов рецепторов к IL-6 способствует снижению показателей смертности и потребности в искусственной вентиляции легких. Кроме того, согласно данным низкой степени убедительности, их применение может способствовать снижению продолжительности пребывания на искусственной вентиляции легких, а также сокращению сроков госпитализации (3)(115)(116). Определенность фактических данных, касающихся риска возникновения серьезных побочных явлений, недостаточна. По данным низкой степени убедительности, риск развития бактериальных инфекций в условиях иммуносупрессивной терапии блокаторами рецепторов к IL-6 может быть сопоставимым с таковым при стандартном лечении (1). Тем не менее, группа по разработке руководящих принципов выразила ряд опасений, связанных с тем, что на фоне непродолжительных сроков катамнестического наблюдения в большинстве исследований, а также трудности точной регистрации нежелательных явлений, таких как бактериальные инфекции или микозы, риски лечения блокаторами рецепторов к IL-6 могут быть недостаточно полно отражены в резюме фактических данных. Кроме того, испытания блокаторов рецепторов к IL-6, которые легли в основу этой рекомендации, преимущественно проводились в странах с высоким уровнем дохода, в которых риск возникновения некоторых инфекционных осложнений может быть меньше, чем в других районах мира, в связи с чем обобщаемость данных о неблагоприятных явлениях вызывает сомнения. Не имеется сведений о сравнении риска вреда по критерию получения пациентами одной либо двух доз блокаторов рецепторов к IL-6. При анализе в подгруппах по критериям применявшегося блокатора рецепторов к IL-6 (сарилумаб или тоцилизумаб) либо тяжести заболевания (тяжелое или крайне тяжелое) модификации эффекта выявлено не было, в связи с чем данная рекомендация действует в отношении всех взрослых пациентов с тяжелой и крайне тяжелой формой COVID-19 (110). Ввиду недостаточного объема данных, проведение анализа в подгруппах по критериям повышения уровня маркеров воспаления, а также возраста не было возможным (см. раздел «Данные по итогам исследования»). По данным анализа в подгруппах по критерию применения стероидов в исходный момент времени были выявлены большие преимущества использования блокаторов рецепторов к IL-6 у пациентов, получавших стероиды, в отличие от пациентов, которые их не получали (p=0,026), что не только подчеркивает возможность применения блокаторов рецепторов к IL-6 на фоне приема стероидов, но и положительный синергизм этих препаратов. Настоятельная рекомендация о применении стероидов у пациентов с тяжелым и крайне тяжелым течением COVID-19 в настоящее время находится в силе, в связи с чем формальная оценка достоверности этих аналитических сведений, полученных в подгруппах, не выполнялась, так как вынесение отдельной рекомендации на уровне подгруппы пациентов, не получающих кортикостероиды, не имело бы оснований. Убедительность фактических данных Степень убедительности фактических данных в отношении показателей смертности и потребности в искусственной вентиляции легких была оценена как высокая. Степень убедительности фактических данных в отношении продолжительности искусственной вентиляции легких была оценена как низкая ввиду серьезного риска систематической ошибки, которая могла иметь место на фоне отсутствия маскировки данных в рассмотренных исследованиях, а также неоднозначности трактовки данных, так как величина нижней границы доверительного интервала указывает на отсутствие эффекта. Степень убедительности фактических данных в отношении продолжительности госпитализации была оценена как низкая ввиду серьезного риска систематической ошибки, которая могла иметь место на фоне отсутствия маскировки данных в рассмотренных исследованиях, а также неединообразия данных, вызванного различиями точечных оценок и отсутствием перекрытия доверительных интервалов. Убедительность данных, касающихся серьезных побочных явлений, была оценена как крайне низкая ввиду отсутствия маскировки данных и ошибок сбора данных, а также крайней неоднозначности трактовки данных в связи с избыточной шириной доверительных интервалов, которая не позволяет исключить важных преимуществ, либо вреда; убедительность данных, касающихся риска бактериальных инфекций или микозов, оценена как низкая в силу похожих соображений, касающихся высокой вероятности риска систематической ошибки и существенной неоднозначности трактовки данных. Степень убедительности фактических данных, полученных при сравнении влияния тоцилизумаба и сарилумаба на показатель смертности, была оценена как умеренная ввиду определенной неоднозначности трактовки данных. Ценностные ориентиры и предпочтения После рассмотрения данных с точки зрения согласованных ценностных ориентиров и предпочтений (см. раздел 7) большинство членов группы по разработке руководящих принципов пришли к выводу о том, что почти все надлежащим образом информированные пациенты предпочтут лечение блокаторами рецепторов к IL-6. Члены группы предположили, что преимущество применения блокаторов рецепторов к IL-6, связанное со снижением смертности, является крайне важным для пациентов, несмотря на крайне низкую степень убедительности данных, которые касаются серьезных побочных явлений. Группа по разработке руководящих принципов предположила, что различия ценностных ориентиров и предпочтений разных пациентов в отношении данного вмешательства будут незначительными. Ресурсная оснащенность и другие аспекты Последствия для ресурсной оснащенности, обеспечения равноправия и соблюдения прав человека Группа по разработке руководящих принципов отметила, что, по сравнению с некоторыми другими кандидатными средствами для лечения COVID-19, блокаторы рецепторов к IL-6 отличаются большей стоимостью, и в рекомендации не учтена ценовая эффективность. В настоящее время доступ к этим препаратам во многих странах мира затруднен, и в отсутствие согласованных усилий данное положение дел, вероятно, сохранится, особенно в слабо обеспеченных ресурсами районах. Таким образом, данная настоятельная рекомендация в отношении блокаторов рецепторов к IL-6 может обострить неравенство в области здравоохранения. С другой стороны, принимая во внимание доказанные преимущества для пациентов, она должна обеспечить стимул для задействования всех возможных механизмов улучшения глобального доступа к этим средствам лечения. Каждая страна может сформулировать собственные рекомендации, принимая во внимание доступные ресурсы, и соответствующим образом определить варианты лечения. 92 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) В период дефицита лекарственных средств может быть необходима приоритизация использования блокаторов рецепторов к IL-6 по механизму клинической сортировки (6). Во многих странах предложены механизмы сортировки для использования этих средств лечения. Они охватывают приоритизацию пациентов, затронутых наивысшим риском смертности в исходный момент времени (например, лица с крайне тяжелым течением инфекции по сравнению с лицами с тяжелым течением), для которых абсолютная польза данного лечения является наибольшей. Например, несмотря на убедительность относительного эффекта применения блокаторов рецепторов к IL-6 (ОШ 0,86 для показателя смертности), риск смертности в абсолютном выражении сокращается на 31 случай на 1000 человек (95% ДИ в диапазоне от снижения на 11 до снижения на 47 случаев летального исхода) в группе лиц с крайне тяжелым течением инфекции и на 13 случаев на 1000 человек (95% ДИ в диапазоне от снижения на 5 до снижения на 19 случаев летального исхода) в группе лиц с тяжелым течением инфекции. Другие предложения, касающиеся приоритизации, однако непосредственно не обоснованные фактическими данными, включают закрепление приоритета за пациентами с активно ухудшающейся динамикой заболевания и отказ от терапии блокаторами рецепторов к IL-6 у лиц с установленной полиорганной недостаточностью (для которых преимущества, по-видимому, будут ниже). Приемлемость и практическая осуществимость Так как блокаторы рецепторов к IL-6 необходимо вводить внутривенно, данное средство лечения следует в первую очередь использовать у пациентов с тяжелым и крайне тяжелым течением COVID-19, которым необходима госпитализация. Блокаторы рецепторов к IL-6 сравнительно просты в использовании и требуют однократного или, в крайнем случае, двукратного введения. Обоснование При вынесении на основании фактических сведений настоятельной рекомендации использовать блокаторы рецепторов к IL-6 (тоцилизумаб или сарилумаб) у пациентов с тяжелым и крайне тяжелым течением COVID-19 группа по разработке руководящих принципов подчеркнула высокий уровень убедительности данных об улучшении выживаемости и снижении потребности в инвазивной искусственной вентиляции легких. Дополнительные данные исследования REMAP-CAP (см. раздел, посвященный резюме данных научных исследований) позволили прийти к более убедительным выводам относительно эквивалентности тоцилизумаба и сарилумаба. Группа по разработке руководящих принципов признала неопределенность сведений, касающихся серьезных побочных явлений и бактериальных инфекций, однако пришла к выводу о том, что наличие данных в пользу преимуществ, касающихся двух наиболее важных для пациентов исходов, позволяет вынести настоятельную рекомендацию. К числу важных соображений относятся аспекты, связанные со стоимостью и обеспечению доступности, и группа признала, что данная рекомендация может усугубить неравенство в вопросах здоровья. Группа надеется, что эта рекомендация создаст стимул для решения указанных проблем и обеспечения доступности в различных регионах и странах. Группа предположила, что значимых различий ценностных ориентиров и предпочтений пациентов выявлено не будет, а другие ситуационные факторы не повлияют на рекомендацию (см. раздел, посвященный фактическим сведениям, лежащим в основе данного решения). Анализ в подгруппах Группа по разработке руководящих принципов не выявила данных за эффекты в подгруппах пациентов с различной тяжестью заболевания (тяжелая или крайне тяжелая форма) либо получающих конкретный препарат группы блокаторов рецепторов к IL-6 (тоцилизумаб или сарилумаб). Объем данных для оценки эффекта в подгруппах по критериям уровня воспалительных маркеров или возраста был недостаточным. Хотя группа по разработке руководящих принципов изучила данные сравнительного анализа в подгруппах пациентов, получавших и не получавших кортикостероиды в исходный момент времени, было решено, что вынесение рекомендаций по блокаторам рецепторов к IL-6 в подгруппах лиц, не получающих кортикостероиды, нецелесообразно, так как все пациенты с тяжелым и крайне тяжелым течением COVID-19 должны получать кортикостероиды (см. ниже текст предыдущей настоятельной рекомендации). Принимая во внимание указанные обстоятельства, группа приняла решение о том, что данная рекомендация применима как к тоцилизумабу, так и сарилумабу и относится ко всем взрослым пациентам с COVID-19 тяжелого или крайне тяжелого течения. Значение блокаторов рецепторов к IL-6 и барицитиниба ВОЗ недавно вынесла настоятельную рекомендацию применять барицитиниб у пациентов с тяжелым и крайне тяжелым течением COVID‑19. Оба класса лекарственных средств являются иммуномодуляторами, влияние которых на иммунный ответ частично дублирует друг друга. Таким образом, существует вероятность того, что их влияние на COVID-19 не будет аддитивным. Кроме того, вероятно, что при совместном назначении препаратов нежелательные эффекты, включая вторичные бактериальные или грибковые инфекции, будут более выраженными. В отсутствие сведений о дополнительной пользе при совместном назначении группа рекомендует клиницистам не применять данные препараты в комбинации. Подробные сведения, касающиеся выбора варианта терапии, см. в разделе обоснования для ингибиторов JAK и соответствующей сводной таблице результатов наблюдений (см. «Данные по итогам исследования»). Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Вместе с тем группа по разработке руководящих принципов не имела оснований предполагать, что ответ на лечение блокаторами рецепторов к IL-6 у детей будет отличаться. Это в значительной степени относится к тоцилизумабу, который безопасно применяется у детей по ряду показаний, включая полиартикулярный вариант ювенильного ревматоидного артрита, системный дебют ювенильного хронического артрита и синдром высвобождения цитокинов, индуцированный Т-клетками с химерным антигенным рецептором. Сарилумаб не одобрен для применения в педиатрии, в связи с чем предпочтительным препаратом группы блокаторов рецепторов к IL-6 в этой популяции может стать 93 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) тоцилизумаб. Кроме того, Группа по разработке руководящих принципов признала, что во многих случаях дети поступают в лечебные учреждения с острыми респираторными заболеваниями, вызванными другими патогенами; в связи с этим даже при получении положительного результата тестирования затруднена диагностика тяжелой формы COVID-19, и, следовательно, выявление лиц, которые могут получить пользу от использования блокаторов рецепторов к IL-6. Подобные соображения относятся и к беременным женщинам: не имеется данных, непосредственно характеризующих эту популяцию, с другой стороны, не имеется оснований предполагать иной ответ на лечение по сравнению с остальными взрослыми пациентами. Тем не менее данный препарат способен проникать через плацентарный барьер, и хотя последствия временной иммуносупрессии плода не выяснены, необходимо соотносить их с потенциальной пользой для матери. Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: барицитиниб Сравнение: Блокаторы рецепторов к интерлейкину-6 Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Блокаторы рецепторов к IL-6 Вмешательство Барицитиниб Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,77 (95% ДИ: 0,53–1,1) На основании данных по 2659 пациентам в 3 исследованиях (рандомизированные контролируемые) 118 на 1000 96 на 1000 Низкая Ввиду существенной неоднозначности трактовки данных и продолжающегося набора в крупное РКИ1 Вероятно, применение барицитиниба приводит к снижению показателя смертности. Разница: сокращение на 22 случая на 1000 (95% ДИ: сокращение на 52 случая – увеличение на 9 случаев) Искусственная вентиляция легких Отношение шансов: 1,01 (95% ДИ: 0,61–1,6) На основании данных по 2434 пациентам в 2 исследованиях (рандомизированные контролируемые) 94 на 1000 96 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных2 Вероятно, влияние на потребность в искусственной вентиляции легких минимально или отсутствует. Разница: увеличение на 2 случая на 1000 (95% ДИ: сокращение на 38 случаев – увеличение на 44 случая) Нежелательные явления, приводящие к отмене препарата На основании данных по 2309 пациентам в 4 исследованиях (рандомизированные контролируемые) 0 на 1000 1 на 1000 Средняя Ввиду существенной неоднозначности трактовки данных3 Предположительно, различия по критерию нежелательных явлений, приводящих к отмене, минимальны или отсутствуют. Разница: увеличение на 1 случай на 1000 (95% ДИ: сокращение на 11 случаев – увеличение на 15 случаев) Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 2652 участникам в 3 исследованиях (рандомизированные контролируемые) 8,1 дня (медианное значение) 11,2 дня (среднее значение) Крайне низкая В связи с высокой вероятностью систематической ошибки, существенным неединообразием данных и крайней неоднозначностью их трактовки4 Влияние на сокращение сроков госпитализации остается крайне неопределенным. Разница: СО: увеличение на 3,1 (95% ДИ: сокращение на 3,8 случая – увеличение на 9,9 случая) Продолжительность искусственной вентиляции легких Меньший показатель предпочтителен На основании данных по: 328 участникам в 2 исследованиях (рандомизированные контролируемые) 13,8 дня (медианное значение) 11,6 дня (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки5 Вероятно, применение барицитиниба способствует сокращению продолжительности искусственной вентиляции легких. Разница: СО: сокращение на 2,2 (95% ДИ: сокращение на 5,3 случая – сокращение на 0,7 случая) Время до клинического улучшения состояния Меньший показатель предпочтителен На основании данных по: 2558 участникам в 2 исследованиях (рандомизированные контролируемые) 8,4 дня (медианное значение) 8,9 дня (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки6 Существенное влияние на сроки до клинического улучшения состояния может отсутствовать. Разница: СО: увеличение на 0,5 (95% ДИ: сокращение на 2,3 случая – увеличение на 3,2 случая) 94 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область несущественных различий. 2. Риск систематической ошибки: серьезный риск отсутствует. Большая часть данных о блокаторах рецепторов к интерлейкину-6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. 3. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область незначительного, однако вместе с тем важного вреда. 4. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину-6 накоплена в исследованиях, в которых имело место раскрытие данных. Неединообразие: существенное. Результаты исследований, посвященных блокаторам рецепторов к интерлейкину-6, противоречивы: прием ряда препаратов приводил к повышению продолжительности госпитализации, тогда как прием других – к сокращению. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область важных преимуществ, так и область серьезного вреда. 5. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину-6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область несущественных различий. 6. Риск систематической ошибки: существенный. Большая часть данных о блокаторах рецепторов к интерлейкину-6 накоплена в исследованиях, в которых имело место раскрытие данных. Неоднозначность трактовки данных: существенная. Доверительный интервал охватывает как область существенного вреда, так и существенных преимуществ (для минимально значимых различий используется пороговое значение 1 день). Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 Вмешательство: блокаторы рецепторов к интерлейкину-6 Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных по блокаторам рецепторов к IL-6 использовались ОДСМА (8) 30 РКИ с участием 10 618 пациентов, на основании которого были получены относительные оценки влияния на важные для пациентов исходы, за исключением показателя смертности, данные о котором получены из проспективного метаанализа (ПМА) (116). Все исследования, включенные в ОДСМА, были зарегистрированными, и в них принимали участие пациенты с тяжелым или крайне тяжелым течением заболевания, связанного с COVID-19 (таблица с описанием исследований предоставляется по запросу). При этом 37% процентов этих исследований были опубликованы в рецензируемых журналах, 3% были доступны в форме предварительной публикации, и 60% были завершены, но не опубликованы. Резюме фактических данных по смертности было основано на ПМА данных 27 РКИ с участием 10 930 пациентов (116). Данные ПМА использовались в отношении показателя смертности, так как они включали дополнительные неопубликованные сведения по этому конечному результату. Группа по разработке руководящих принципов отметила, что стандартный порядок оказания помощи, возможно, отличается в различных центрах и районах, а также изменяется с течением времени. Тем не менее, принимая во внимание поступление всех данных из РКИ, необходимо обеспечить сбалансированность между группами пациентов, рандомизированных в группу исследуемого препарата или лечения по стандарту, по критерию назначения сопутствующих видов лечения, которые относятся к стандарту оказания помощи. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения блокаторов рецепторов к IL-6 для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах Во всех рассмотренных исследованиях применение блокаторов рецепторов к IL-6 оценивалось исключительно у взрослых, нуждавшихся в госпитализации, с тяжелым или крайне тяжелым течением COVID-19. Группа по разработке руководящих принципов запросила выполнение анализа в подгруппах по критериям возраста (моложе 70 лет и старше 70 лет), тяжести течения заболевания (тяжелое или крайне тяжелое), уровня воспалительных маркеров и факта использования кортикостероидов в исходный момент времени в разбивке по следующим конечным результатам: смертность, потребность в искусственной вентиляции и ее продолжительность, продолжительность госпитализации, а также риски серьезных побочных явлений и бактериальных инфекций. На основании анализа в подгруппах группа по разработке руководящих указания пришла к выводу об отсутствии эффекта в подгруппах по критерию тяжести заболевания применительно к любому из заранее определенных конечных результатов. Группа рассмотрела данные анализа в подгруппах во всех охваченных исследованиях по критерию использования системных кортикостероидов, определив смертность как искомый конечный результат. Аналитические данные указывают на то, что относительные эффекты блокаторов рецепторов к IL-6 были различными в зависимости от применения системных кортикостероидов в исходный момент времени. Важно заметить, что с точки зрения снижения смертности применение стероидов не исключает и даже усиливает положительный эффект блокаторов рецепторов к IL-6. В силу указанных ниже обстоятельств группа по разработке руководящих принципов не проводила формальную оценку достоверности этих аналитических сведений в подгруппах. 95 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) При сравнении тоцилизумаба и сарилумаба на основе ПМА данных за эффект в подгруппах получено не было (116). Вместе с тем объем данных, полученных в сравнении комбинации «тоцилизумаб+стероиды» с приемом только стероидов (ОШ 0,77; 95% ДИ: 0,68–0,87), превышает (и, следовательно, обеспечивает большую точность) объем данных, полученных в сравнении комбинации «сарилумаб+стероиды» с приемом только стероидов (ОШ 0,92; 95% ДИ: 0,61–1,38). В дополнение к этим данным в подгруппах группа по разработке руководящих принципов рассмотрела результаты прямого сравнения, выполненного в ходе исследования REMAP-CAP, которое не показало различий между тоцилизумабом и сарилумабом в популяции пациентов, получающих кортикостероиды (величина показателя смертности: 36,5% в группе лечения тоцилизумабом и 33,9% в группе лечения сарилумабом). Сравнительная оценка в рамках СМА комбинаций «тоцилизумаб+стероиды» и «сарилумаб+стероиды», в которой учитывались как прямые, так и косвенные данные, позволила получить данные средней степени убедительности об отсутствии различий в эффекте данных препаратов (ОШ 1,07; 95% ДИ: 0,86–1,34) (1)(3). Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательств о Блокаторы рецепторов к IL-6 Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность (пациенты с тяжелой и крайне тяжелой формой заболевания) Отношение шансов: 0,86 (95% ДИ: 0,79–0,95) Данные по 10 930 пациентам, полученные в 27 исследованиях1 (рандомизированные контролируемые) 130 на 1000 114 на 1000 Высокая применение блокаторов рецепторов к IL‑6 приводит к снижению смертности. Разница: сокращение на 16 случаев на 1000 (95% ДИ: сокращение на 24 случая – сокращение на 6 случаев) Искусственная вентиляция легких Отношение шансов: 0,72 (95% ДИ: 0,57–0,9) Данные по 5686 пациентам, полученные в 9 исследованиях2 (рандомизированные контролируемые) 86 на 1000 63 на 1000 Высокая Применение блокаторов рецепторов к IL‑6 приводит к снижению потребности в искусственной вентиляции легких. Разница: сокращение на 23 случая на 1000 (95% ДИ: сокращение на 35 случаев – сокращение на 8 случаев) Нежелательные явления, приводящие к отмене препарата Отношение шансов: 0,5 (95% ДИ: 0,03–9,08) Данные по 815 пациентам, полученные в 2 исследованиях3 (рандомизированные контролируемые) 9 на 1000: 5 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки и крайней неоднозначностью трактовки данных4 Влияние блокаторов рецепторов к IL-6 на развитие нежелательных явлений, приводящих к отмене препарата, не определено Разница: сокращение на 4 случая на 1000 (95% ДИ: увеличение на 0 случаев – увеличение на 67 случаев) Бактериальные инфекции Отношение шансов: 0,95 (95% ДИ: 0,72–1,29) Данные по 3548 пациентам, полученные в 18 исследованиях (рандомизированные контролируемые) 101 на 1000 96 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных5 Применение блокаторов рецепторов к IL‑6 может не приводить к увеличению частоты вторичных бактериальных инфекций. Разница: сокращение на 5 случаев на 1000 (95% ДИ: сокращение на 26 случаев – увеличение на 26 случаев) Продолжительность искусственной вентиляции легких Предпочтителен более низкий уровень На основании данных по: 1189 пациентам в 10 исследованиях (рандомизированные контролируемые) 14,7 (среднее значение) 13,5 (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных 6 Блокаторы рецепторов к IL-6 могут способствовать сокращению продолжительности искусственной вентиляции легких. Разница: СР ниже на 1,2 (95% ДИ: ниже на 2,3 – ниже на 0,1) Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 6665 пациентам в 9 исследованиях (рандомизированные контролируемые) 12,8 (среднее значение) 8,3 (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и существенного неединообразия7 Блокаторы рецепторов к IL-6 могут способствовать сокращению продолжительности госпитализации. Разница: СР ниже на 4,5 (95% ДИ: ниже на 6,7 – ниже на 2,3) 96 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Уровень для сравнения/группа сравнения: первичное исследование [15]. Величины исходного риска смертности и искусственной вентиляции легких получены из исследования ВОЗ SOLIDARITY для пациентов с тяжелой и крайне тяжелой формами COVID-19, сделаны поправки на применение кортикостероидов в рамках стандарта оказания помощи (16% исходный риск x ОР 0,79 для кортикостероидов = 13%). По мнению членов группы по разработке руководящих принципов, контрольная группа исследования SOLIDARITY, проводившегося в большом ряде стран и географических районов, в целом служит наиболее актуальным источником фактических данных для оценки исходного риска смертности и искусственной вентиляции легких у пациентов с тяжелой и крайне тяжелой формами COVID-19. 2. Систематический обзор [3]. Уровень для сравнения/группа сравнения: первичное исследование. Величины исходного риска смертности и искусственной вентиляции легких получены из исследования ВОЗ SOLIDARITY для пациентов с тяжелой и крайне тяжелой формами COVID-19, сделаны поправки на применение кортикостероидов в рамках стандарта оказания помощи (16% исходный риск x ОР 0,79 для кортикостероидов = 13%). По мнению членов группы по разработке руководящих принципов, контрольная группа исследования SOLIDARITY, проводившегося в большом ряде стран и географических районов, в целом служит наиболее актуальным источником фактических данных для оценки исходного риска смертности и искусственной вентиляции легких у пациентов с тяжелой и крайне тяжелой формами COVID-19. 3. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Применялась медианная частота событий для всех пациентов, которые были рандомизированы в группу стандартного лечения во всех рассмотренных исследованиях. Справочные материалы: [3], 4. Риск систематической ошибки: существенный. Присвоен более низкий ранг в связи с наличием риска систематической ошибки из-за отсутствия маскировки данных и ошибки сбора данных. Неоднозначность трактовки данных: крайняя. Присвоен более низкий ранг в связи с чрезмерной шириной доверительных интервалов, которые накрывают нулевое значение. 5. Риск систематической ошибки: существенный. Присвоен более низкий ранг в связи с наличием риска систематической ошибки из-за отсутствия маскировки данных и ошибки сбора данных. Неоднозначность трактовки данных: существенная. Присвоен более низкий ранг в связи с шириной доверительных интервалов, которые накрывают нулевое значение. 6. Риск систематической ошибки: существенный. Присвоен более низкий ранг в связи с наличием риска систематической ошибки из-за отсутствия маскировки данных. Неоднозначность трактовки данных: существенная. Присвоен более низкий ранг, так как нижняя граница доверительного интервала близка к нулевому значению. 7. Риск систематической ошибки: существенный. Присвоен более низкий ранг в связи с наличием риска систематической ошибки из-за отсутствия маскировки данных. Неединообразие: существенное. Присвоен более низкий ранг в связи с различиями точечных оценок и отсутствием перекрытия доверительных интервалов. 6.11.1. Механизм действия IL-6 является цитокином с плейотропным эффектом, ответственным за активацию и регуляцию иммунного ответа на инфекцию. Отмечена взаимосвязь повышения концентрации IL-6 с возникновением тяжелых последствий COVID-19, включая дыхательную недостаточность и летальный исход, хотя роль IL-6 в патогенезе заболевания неясна. Тоцилизумаб и сарилумаб являются препаратами моноклональных антител, которые одобрены для использования при ревматоидном артрите. Они являются антагонистами мембраносвязанных и растворимых форм рецептора к IL-6 (IL-6R/sIL- 6R). Тоцилизумаб разрешен для внутривенного введения при ревматоидном артрите, тогда как сарилумаб – для подкожного введения, хотя для лечения COVID-19 изучалось внутривенное применение обоих препаратов. На основании исследований, посвященных ревматоидному артриту (29), полагают, что при COVID-19 оба препарата в изученных дозах позволят обеспечить крайне высокое связывание с рецепторами. В настоящее время блокаторы рецепторов к IL-6 перепрофилируют с точки зрения их показаний, но не основного механизма, обусловливающего фармацевтические эффекты. Эффективность при COVID-19 зависит от важности сигнального пути, опосредованного IL-6, в патофизиологическом каскаде заболевания, нежели достижением целевой концентрации препарата при введении в используемых дозах. 97 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.12. Ивермектин (опубликовано 31 марта 2021 г.) Справочная информация Рекомендации в отношении ивермектина были опубликованы 31 марта 2021 г. в четвертой версии вариативных рекомендаций ВОЗ, а также в журнале BMJ в разделе "Rapid Recommendations". Документ был подготовлен в связи с возросшим интересом международной общественности к ивермектину как потенциальному средству лечения. В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся ивермектина, внесено не было. Экспертной группе известно, что с момента вынесения предыдущей рекомендации были опубликованы результаты ряда новых исследований сравнительно небольшого масштаба и результаты одного из основных клинических испытаний были признаны недействительными ввиду опасений по поводу манипулирования данными (117)(118). Тем не менее обновленное резюме фактических данных, составленное на основе ОДСМА, не противоречит вынесенной ранее рекомендации. Это обновленное резюме будет в полной мере учтено экспертной группой в следующих пересмотренных версиях данного рекомендательного документа. Госпитализированные пациенты с COVID-19, независимо от тяжести заболевания Практические сведения Группой сделана рекомендация не применять ивермектин для лечения пациентов с COVID-19 вне клинических испытаний, в связи с чем разработка практических соображений по использованию этого препарата малоактуальна. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Влияние применения ивермектина на показатели смертности, искусственной вентиляции легких, госпитализации, продолжительности госпитализации и элиминации вируса остается неясным ввиду крайне низкой степени убедительности данных в отношении каждого из этих исходов. Влияние применения ивермектина на время до клинического улучшения состояния может быть слабым или отсутствовать (низкая степень убедительности данных). Применение ивермектина, вероятно, повышает риск серьезных побочных явлений, приводящих к отмене препарата (низкая степень убедительности данных). При анализе в подгруппах данных за модификацию эффекта в зависимости от дозы получено не было. Ввиду недостаточного объема данных проведение анализа в подгруппах по критериям возраста пациентов или тяжести заболевания не было возможным (см. раздел «Данные по итогам исследования»). Таким образом, во всех подгруппах ожидается сходство эффектов. Эта рекомендация относится к пациентам с любой тяжестью заболевания и любой продолжительностью проявления симптоматики. Убедительность фактических данных По мнению группы по разработке руководящих принципов, фактические сведения в отношении большинства важных исходов, включая смертность, потребность в искусственной вентиляции легких, потребность в госпитализации, продолжительность госпитализации и элиминации вируса, характеризовались крайне низкой степенью убедительности. Степень убедительности фактических данных была оценена как крайне низкая в первую очередь ввиду крайней неоднозначности трактовки сведений о большинстве исходов: доверительные интервалы для сводных данных были широкими и/или было зарегистрировано крайне малое количество событий. Кроме того, серьезную обеспокоенность вызывал риск систематической ошибки для некоторых исходов, особенно отсутствие маскировки данных, отсутствие предварительной регистрации исследования и отсутствие учета исходов в одном из исследований: в нем не сообщалось о потребности в искусственной вентиляции легких, несмотря на указание данного параметра в протоколе (искаженная публикация). Только в условиях проведения исследований Авторы не рекомендуют применение ивермектина у пациентов с COVID-19 за исключением случаев клинических испытаний (рекомендуется применять только в условиях проведения научных исследований). Примечание. Эта рекомендация относится к пациентам с любой тяжестью заболевания и любой продолжительностью проявления симптоматики. Рекомендация использовать препарат в условиях клинических испытаний целесообразна в случае, если на фоне фактических данных крайне низкой степени убедительности планируется проведение научных изысканий, обладающих большим потенциалом для уточнения эффектов искомого вмешательства при разумных издержках. 98 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Подробные сведения представлены в разделе, посвященном обоснованию данной рекомендации. Степень убедительности данных в отношении других исходов, включая серьезные побочные явления и время до клинического улучшения состояния, была оценена как низкая. Ценностные ориентиры и предпочтения Опираясь на согласованный перечень ценностных ориентиров и предпочтений (см. раздел 7), группа по разработке руководящих принципов предположила, что, с учетом крайне высокой неопределенности фактических данных в отношении показателей смертности, потребности в искусственной вентиляции легких, потребности в госпитализации и других значимых исходах, представляющих интерес, а также на фоне возможного вреда, например побочных явлений, связанных с лечением, практически все надлежащим образом информированные пациенты будут склонны получать ивермектин только в условиях рандомизированного исследования. По мнению экспертной группы, различия ценностных ориентиров и предпочтений, касающихся данного вмешательства, у разных пациентов будут незначительными. Ресурсная оснащенность и другие аспекты Ивермектин является сравнительно недорогим и широкодоступным средством, в том числе в странах с низким уровнем дохода. По мнению группы, низкая стоимость и широкая доступность не означают необходимости применения препарата, который характеризуется слабо подтвержденными преимуществами и вероятностью вреда. Хотя стоимость в пересчете на одного пациента может быть невысокой, группа по разработке руководящих принципов выразила обеспокоенность в связи с риском отвлечения усилий и ресурсов от мероприятий, которые с высокой вероятностью могут принести пользу, таких как применение кортикостероидов для лечения пациентов с тяжелым течением COVID-19 и другие меры поддерживающего ухода. Кроме того, использование ивермектина для лечения COVID-19 может привести к снижению его доступности в сферах, для которых он разработан, и дефициту, особенно в программах по контролю и ликвидации гельминтозов. Необходимо также принять во внимание наличие у пациента эндемичных инфекционных заболеваний, течение которых может усугубиться на фоне приема кортикостероидов. В районах, эндемических по стронгилоидозу, допускается эмпирическое назначение ивермектина на усмотрение лечащего врача пациентам, которые получают лечение стероидами по поводу COVID-19, хотя такое назначение не будет связано собственно с COVID-19. Обоснование При вынесении на основании фактических данных рекомендации использовать ивермектин у пациентов с COVID-19 исключительно в условиях клинического испытания, группа по разработке руководящих принципов подчеркнула существенную неопределенность данных в отношении большинства важных исходов, таких как смертность и потребность в искусственной вентиляции легких. Кроме того, группой отмечено наличие фактических данных, указывающих на возможные отрицательные эффекты лечения, которые проявляются повышением часты нежелательных явлений. Группа по разработке руководящих принципов исходила из предположения о том, что среди пациентов не будет выявлено существенных различий ценностных ориентиров и предпочтений. Экспертная группа также подчеркнула, что другие факторы, такие как наличие ресурсов, доступность, практическая осуществимость и влияние на справедливость в вопросах здоровья, не сказались на данной рекомендации. По сравнению с другими препаратами, оценка которых проводилась в рамках вариативных рекомендаций ВОЗ «Лекарственная терапия при COVID-19», в настоящее время в отношении ивермектина имеется существенно меньше данных из РКИ. Кроме того, существующие данные по ивермектину характеризуются существенно меньшей степенью убедительности, в том числе в связи с набором в исследования меньшего количества пациентов и меньшим количеством учтенных событий. Высокая степень неопределенности Убедительность оценки эффектов ивермектина в отношении основных исходов, представляющих интерес, включая смертность, крайне низка, в связи с чем влияние ивермектина на эти исходы остается неопределенным. Наличию неопределенности способствуют две группы факторов: существенный риск систематической ошибки, а также существенная неоднозначность трактовки данных. Хотя для подготовки резюме рекомендаций по данному препарату использовались сведения 16 РКИ, только в пяти из них имело место непосредственное сравнение ивермектина со стандартом оказания помощи и проводился учет смертности (119)(120)(121)(122)(123)(124)(125). Необходимо заметить, что, в соответствии с принятой методологией, группа по проведению ОДСМА исключила из рассмотрения псевдорандомизированные исследования, а также любые РКИ, в которых методики рандомизации не использовались в явном виде. В двух (119)(120) из пяти перечисленных РКИ отмечался риск систематической ошибки в связи с ненадлежащей маскировкой данных. Кроме того, набор и рандомизация пациентов в одно (119) из этих двух исследований были начаты до обнародования протокола, что дополнительно способствует повышению риска систематической ошибки. Примером потенциального влияния риска систематической ошибки служит анализ смертности в подгруппах на основе риска систематической ошибки в исследовании. Как показано на лесовидной диаграмме (рисунок 3), совокупная оценка всех пяти РКИ, в которых непосредственно сравнивалось применение ивермектина со стандартом оказания помощи, указывает на снижение смертности на фоне приема ивермектина, однако данный эффект будет неявным при учете исключительно тех исследований, в которых риск систематической ошибки низок (на их долю в общей сложности приходится порядка двух третьих фактических данных). В свете этого наблюдения степень неопределенности в отношении истинного влияния ивермектина на показатель смертности еще более повышается. Аналогичное явление наблюдается не только в случае прямых, но и косвенных данных сравнения ивермектина со стандартом оказания помощи (сравнения с гидроксихлорохином и комбинацией лопинавира и ритонавира). Косвенные данные, указывающие на снижение показателя смертности на фоне приема ивермектина, практически полностью основаны на одном исследовании, в котором весьма высок риск систематической ошибки (117) в связи с отсутствием подробного описания процедуры маскировки данных и рандомизации, а также отсутствия обнародованного протокола исследования (схема не представлена). 99 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Рисунок 3. Лесовидная диаграмма, отражающая результаты прямого сравнения ивермектина со стандартом оказания помощи по критерию смертности в подгруппах в разбивке по риску систематической ошибки IV: обратная дисперсия. Помимо риска систематической ошибки при определении смертности также имеется обеспокоенность относительно неоднозначности трактовки данных. Согласно методологии GRADE, неопределенность оценивают на основе доверительного интервала, а также ориентировочного объема информации (количество событий) при наличии подходящих сведений для подготовки обоснованных решений (126). В данном случае, несмотря на величину доверительных интервалов, которые указывают на преимущество ивермектина, объем информации был крайне малым. Основой для определения смертности (не принимая во внимание все рассмотренные выше аспекты риска систематической ошибки) служит 9 летальных исходов в группе 511 пациентов, рандомизированных в группу ивермектина (1,76%) и 22 летальных исхода в группе 404 пациентов, рандомизированных в группу стандарта оказания помощи (5,45%). Данное количество событий крайне мало для обоснования выводов и существенно отличается от оптимального объема информации. Выполнение теоретического расчета, в котором три события (летальных исхода) переносят из рандомизированной группы стандарта оказания помощи в рандомизированную группу ивермектина, приводит к исчезновению статистической значимости, что указывает на возможное появление результатов исключительно в силу случайности. Кроме того, фактические данные, лежащие в основе этого сравнения, поступили из ряда небольших исследований, что увеличивает риск невыявленной несбалансированности групп исследования. Принимая во внимание высокую вероятность случайных факторов в полученных наблюдениях, экспертная группа предположила, что имеется крайняя неоднозначность трактовки данных, которая в еще большей степени снижает их убедительность. Невзирая на то, что точечные оценки и доверительные интервалы указывают на возможную пользу применения ивермектина, фактические сведения в отношении смертности были охарактеризованы как обладающие крайне низкой степенью убедительности в связи с сочетанием высокого риска систематической ошибки и крайней неоднозначности трактовки данных. Таким образом, группа пришла к выводу о том, что влияние ивермектина на показатель смертности является неопределенным. При рассмотрении других важных исходов, включая искусственную вентиляцию легких, госпитализацию и длительность госпитализации, были приняты во внимание аналогичные соображения и получены выводы о крайне низкой степени убедительности данных, относящихся к этим исходам. Анализ в подгруппах Анализ в подгруппах проведен только по критерию эффекта различных дозировок ивермектина; признаков эффекта в подгруппах экспертной группой не выявлено (см. раздел «Данные по итогам исследования»). Ввиду отсутствия сравнений внутри отдельных следований, группа не имела возможности проведения анализа по критерию возраста или тяжести заболевания. Таким образом, рекомендаций в подгруппах для данного лекарственного средства не предложено. Иными словами, рекомендация не применять ивермектин, за исключением случаев клинических испытаний, применима для лиц с различной тяжестью заболевания и различных возрастов и касается всех режимов дозирования ивермектина. Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети до 15 лет, в связи с этим применимость данной рекомендации к детям остается невыясненной. Тем не менее экспертная группа не имела оснований предполагать, что ответ на лечение ивермектином у детей будет отличаться. Подобные соображения относятся и к беременным женщинам: не имеется данных, непосредственно характеризующих эту популяцию, с другой стороны, не имеется оснований предполагать иной ответ на лечение по сравнению с остальными взрослыми пациентами. 100 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с COVID-19 (любая тяжесть заболевания) Вмешательство: ивермектин Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных по ивермектину использовались ОДСМА 16 исследований с участием 2407 пациентов. В 75% рассмотренных исследований изучались пациенты с нетяжелым течением заболевания, и в 25% – как с тяжелым, так и нетяжелым. В ряде рассмотренных исследований не сообщалось об исходах, представлявших интерес для экспертной группы. Двадцать пять процентов этих исследований были опубликованы в рецензируемых журналах, 44% были доступны в форме предварительной публикации, и 31% были завершенными, но не опубликованными (см. таблицу с описанием характеристик исследований). Экспертной группой исключен ряд квази-РКИ (псевдорандомизированных исследований) (127)(128)(129)(130). В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения ивермектина для лечения пациентов с COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах Группа по проведению СМА выполнила анализ в подгруппах, результатом которого может стать вынесение различных рекомендаций в разбивке по подгруппам. На основании имеющихся данных, выполнение анализа в подгруппах было возможным только по критерию дозировки ивермектина и в разбивке по следующим исходам: смертность, искусственная вентиляция легких, госпитализация, нежелательные явления, приводящие к отмене препарата. Анализ дозировки ивермектина в подгруппах был проведен на основании прямого сравнения ивермектина со стандартом оказания помощи. Для целей этого анализа использовалась мета-регрессия в целях оценки эффекта кумулятивной дозы в качестве непрерывной переменной с дополнительным включением ковариаты, характеризующей режимы терапии с введением одной либо нескольких доз. В основу этого подхода была положена информация от специалистов в области фармакологии (под руководством профессора Эндрю Оуэна), который выполнил фармакокинетическое симуляционное моделирование для различных доз, применявшихся в исследованиях, и установил, что при отдельном рассмотрении исследований со введением одной дозы и нескольких доз целесообразно ожидать корреляции кумулятивной дозы ивермектина с основными фармакокинетическими параметрами. Необходимо заметить, что в рассмотренных исследованиях фармакокинетика ивермектина не изучалась непосредственно, и принятый в данной публикации подход основан на симуляционном моделировании и, по возможности, валидации наблюдений с использованием опубликованных сведений о фармакокинетике у человека. Для оценки достоверности результатов исследования, полученных в подгруппах, экспертная группа опиралась на заранее разработанный механизм, включающий инструмент ICEMAN (110). Группа по разработке руководящих принципов запросила выполнение анализа в подгруппах на основе критериев возраста (дети, лица молодого возраста, лица старшего возраста (≥70 лет); тяжести течения заболевания (нетяжелое течение, тяжелое течение, крайне тяжелое течение COVID-19); времени, прошедшего с момента появления симптомов и использования других лекарственных препаратов. Вместе с тем малый объем данных внутри отдельных исследований не позволял выполнить какой-либо из указанных видов анализа в подгруппах по заранее определенному протоколу. Группа отметила, что стандартный порядок оказания помощи, вероятно, отличается в различных центрах и районах, а также изменяется с течением времени. Тем не менее, принимая во внимание поступление всех данных из РКИ, необходимо обеспечить сбалансированность между группами пациентов, рандомизированных в группу исследуемого препарата или лечения по стандарту, в части назначения сопутствующих видов лечения, относящихся к стандарту оказания помощи. Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство ивермектин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 0,19 (95% ДИ: 0,09–0,36) На основании данных по 1419 пациентам в 7 исследованиях1 (рандомизированные контролируемые) 70 на 1000 14 на 1000 Крайне низкая В связи с высокой вероятностью систематической ошибки и крайней неоднозначностью трактовки данных2 Влияние ивермектина на смертность не определено. Разница: сокращение на 56 случаев на 1000 (ДИ 95% сокращение на 63 случая – сокращение на 44 случая) 101 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство ивермектин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Искусственная вентиляция легких Отношение шансов: 0,51 (95% ДИ: 0,12–1,77) На основании данных по 687 пациентам в 5 исследованиях (рандомизированные контролируемые) 20 на 1000 10 на 1000 Крайне низкая Ввиду существенной неоднозначности трактовки данных и искажений публикации3 Влияние ивермектина на вентиляцию легких не определено. Разница: сокращение на 10 случаев на 1000 (95% ДИ: сокращение на 18 случаев – увеличение на 15 случаев) Элиминация вируса 7 дней Отношение шансов: 1,62 (95% ДИ: 0,95–2,86) На основании данных по 625 пациентам в 6 исследованиях (рандомизированные контролируемые) 500 на 1000 618 на 1000 Низкая Ввиду существенного неединообразия и неоднозначности трактовки данных Применение ивермектина может усиливать либо не оказывать эффекта на элиминацию вируса Разница: увеличение на 118 случаев на 1000 (95% ДИ: сокращение на 13 случаев – увеличение на 241 случай) Госпитализация (только амбулаторные пациенты) Отношение шансов: 0,36 (95% ДИ: 0,08–1,48) Данные по 398 пациентам, полученные в 1 исследовании (рандомизированные контролируемые) 50 на 1000 18 на 1000 Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных5 Влияние ивермектина на госпитализацию не определено. Разница: сокращение на 32 случая на 1000 (ДИ 95% сокращение на 47 случаев – увеличение на 23 случая) Серьезные побочные явления Отношение шансов: 3,07 (95% ДИ: 0,77–12,09) На основании данных по 584 пациентам в 3 исследованиях (рандомизированные контролируемые) 9 на 1000 27 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных6 Применение ивермектина может повышать риск развития серьезных побочных явлений, приводящих к отмене препарата. Разница: увеличение на 18 случаев на 1000 (95% ДИ: увеличение на 0 случаев – увеличение на 89 случаев) Время до клинического улучшения состояния Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 633 участникам в 2 исследованиях (рандомизированные контролируемые) 11 дней (среднее значение) 10,5 дня (среднее значение) Низкая Ввиду крайней неоднозначности трактовки данных7 Предположительно ивермектин оказывает слабое влияние либо не оказывает влияние на время до клинического улучшения состояния. Разница: СО: сокращение на 0,5 (95% ДИ: сокращение на 1,7 случая – увеличение на 1,1 случая) Продолжительность госпитализации Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 252 участникам в 3 исследованиях (рандомизированные контролируемые) 12,8 дня (среднее значение) 11,7 дня (среднее значение) Крайне низкая Ввиду существенной неоднозначности трактовки данных и существенного риска систематической ошибки8 Влияние ивермектина на продолжительность госпитализации не определено. Разница: СО: сокращение на 1,1 (95% ДИ: сокращение на 2,3 случая – увеличение на 0,1 случая) Время до элиминации вируса Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 559 участникам в 4 исследованиях (рандомизированные контролируемые) 7,3 дня (среднее значение) 5,7 дня (среднее значение) Крайне низкая Ввиду крайней неоднозначности трактовки данных и высокого риска систематической ошибки9 Характер воздействия применения ивермектина на время до элиминации вируса не может быть достоверно установлен. Разница: СО: сокращение на 1,6 (95% ДИ: сокращение на 4,1 случая – увеличение на 3 случая) 102 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 1. Систематический обзор [1]. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. По мнению членов группы по разработке руководящих принципов, контрольная группа исследования SOLIDARITY отражает стандарт оказания помощи во всех странах, участвовавших в исследовании. 2. Риск систематической ошибки: существенный. Крупное исследование, на основе которого в значительной степени была подготовлена оценка эффекта, строилось на малых исследованиях без маскировки данных. Неоднозначность трактовки данных: крайняя. Совокупное количество событий было крайне малым. 3. Неоднозначность трактовки данных: крайняя. Крайне низкое количество событий и попадание как важных преимуществ, так и вреда в доверительный интервал. Искажение публикации: существенное. 4. Неединообразие: существенное. Точечные оценки существенно различались; значимого перекрытия доверительных интервалов не наблюдалось. Неоднозначность трактовки данных: существенная. Доверительный интервал накрывает область отсутствия эффекта. 5. Неоднозначность трактовки данных: крайняя. Как важные преимущества, так и вред попадают в доверительный интервал. 6. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает область минимальных различий, а также отсутствия различий. 7. Неоднозначность трактовки данных: крайняя. 8. Риск систематической ошибки: существенный. Результат получен на основании одного исследования без маскировки данных. Неединообразие: существенное. Несмотря на перекрытие доверительных интервалов, точечные оценки не согласованы. Неоднозначность трактовки данных: существенная. Доверительные интервалы не накрывают области различий. 9. Риск систематической ошибки: существенный. Имеются основания предполагать риск систематической ошибки. Неоднозначность трактовки данных: крайняя. Доверительный интервал накрывает как область существенных преимуществ, так и существенного вреда. 6.12.1. Механизм действия Ивермектин является противопаразитарным средством, которое нарушает функционирование нервов и мышц гельминтов посредством связывания с глутамат-зависимыми хлоридными каналами (131). На основании лабораторных экспериментов ряд исследователей предположил, что ивермектин может оказывать прямое противовирусное действие в отношении вируса SARS-CoV-2. Вместе с тем при использовании препарата у человека в дозах, рекомендованных при COVID-19, маловероятно достижение концентрации, необходимой для ингибирования вируса в условиях in vitro (132)(133)(134). При изучении инфекции, вызванной вирусом SARS-CoV-2, на модели переднеазиатских хомяков, влияния ивермектина на уровень определяемой РНК вируса SARS-CoV-2 выявлено не было (135). Возможный механизм действия по-прежнему не выяснен: обсуждаются различные мишени, либо на основе аналогии с другими вирусами, жизненный цикл которых существенно отличается, либо, как в случае с несколькими сотнями других кандидатов, на основании симуляционных моделей, которые указывают на возможность молекулярного докинга с целым рядом вирусных мишеней, включая спайк-белок, а также белки RdRp и 3CLpro (136)(137)(138)(139)(140). Прямых доказательств в пользу какого-либо механизма противовирусного действия в отношении вируса SARS-CoV-2 в настоящее время не имеется. По предположению ряда авторов, преимущественно на основании исследований применения препарата по другим показаниям, ивермектин оказывает иммуномодулирующее действие, однако его механизм также не выяснен. Архивные данные свидетельствуют о том, что ивермектин улучшает выживаемость мышей при введении липополисахарида в летальной дозе (141) и оказывает благотворное воздействие в мышиных моделях атопического дерматита и аллергической астмы (142)(143). Одна из гипотез в отношении инфекции, вызванной вирусом SARS-CoV-2, указывает на возможность иммуномодулирующего действия, опосредованного аллостерической модуляцией никотинового ацетилхолинового рецептора альфа-7 (косвенно, путем модификации активности лигандов рецептора). Хотя данный эффект был продемонстрирован исследователями in vitro, применявшиеся в эксперименте концентрации превышали необходимые для противовирусного действия (144), и, следовательно, они крайне трудно достижимы у человека. В модели инфекции, вызванной вирусом SARS-CoV-2, у переднеазиатских хомяков применение ивермектина приводило к определенным изменениям фенотипа иммунного ответа в ткани легких, который согласуется с аллостерической модуляцией никотинового ацетилхолинового рецептора альфа-7 (135). Вместе с тем применение ивермектина не препятствовало снижению массы тела, что являлось важным показателем патологического процесса в данной модели, а также не определялась концентрация препарата в целях дальнейшей экстраполяции для определения у человека. Учитывая изложенные обстоятельства, сохраняется существенная неопределенность в отношении практически значимого иммуномодулирующего или противовоспалительного действия ивермектина. 103 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.13. Гидроксихлорохин (опубликовано 17 декабря 2020 г.) Справочная информация Рекомендации в отношении гидроксихлорохина были опубликованы 17 декабря 2020 г. в третьей версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Документ подготовлен в связи с выходом в свет предварительной версии публикации о результатах исследования ВОЗ SOLIDARITY 15 октября 2020 г., в которой описаны результаты лечения ремдесивиром, гидроксихлорохином и комбинацией лопинавира и ритонавира пациентов, госпитализированных по поводу COVID-19 (15). В одиннадцатой версии (данное издание) документа изменений в рекомендации, касающиеся гидроксихлорохина, внесено не было. Госпитализированные пациенты с COVID-19, независимо от тяжести заболевания Практические сведения Группа по разработке руководящих принципов вынесла настоятельную рекомендацию не применять гидроксихлорохин или хлорохин для лечения пациентов с COVID-19. Прием гидроксихлорохина может препятствовать назначению других важных препаратов, которые также приводят к удлинению интервала QT, например азитромицина и фторхинолонов. Одновременное назначение препаратов, приводящих к удлинению интервала QT, должно производиться с осторожностью. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Вероятно, применение гидроксихлорохина и хлорохина не приводит к снижению показателя смертности или потребности в искусственной вентиляции легких и может не приводить к сокращению сроков госпитализации. Фактические данные не позволяют исключить вероятность более высокого риска летального исхода или перевода пациента на искусственную вентиляцию легких на фоне применения гидроксихлорохина. Влияние на другие, менее важные конечные результаты, в том числе продолжительность периода до исчезновения симптомов, необходимость госпитализации или продолжительность искусственной вентиляции легких, остается неопределенным. Применение гидроксихлорохина может повышать риск возникновения диареи и тошноты или рвоты, что согласуется с наблюдениями, которые получены у пациентов, принимающих препарат по другим показаниям. Диарея и рвота могут повышать риск развития гиповолемии, гипотонии и острого повреждения почек, особенно в условиях ограниченности ресурсов здравоохранения. Способность гидроксихлорохина повышать риск развития кардиотоксичности, в том числе провоцировать жизнеугрожающие аритмии, а также степень такого влияния в настоящее время окончательно не установлены. По данным анализа в подгруппах, модификации эффекта в зависимости от тяжести заболевания (сравнение лиц с крайне тяжелым и тяжелым/нетяжелым течением заболевания, либо с нетяжелым и крайне тяжелым/тяжелым течением заболевания) или возраста (сравнение лиц в возрасте до 70 лет с лицами в возрасте старше 70 лет) не наблюдалось. Кроме того, величина кумулятивной дозы и расчетная величина минимальной концентрации в сыворотке крови на третий день лечения не приводили к модификации эффекта в отношении любого из конченых результатов. Таким образом, во всех подгруппах ожидается сходство эффектов. Кроме того, был выполнен обзор фактических данных, касающихся сравнительного применения гидроксихлорохина в сочетании с азитромицином и отдельно гидроксихлорохина. Фактических данных о способности азитромицина приводить к модификации эффекта гидроксихлорохина в отношении какого‑либо конечного результата выявлено не было (крайне низкая степень убедительности). Убедительность фактических данных Экспертная группа расценила степень убедительности фактических данных, относящихся к важным показателям смертности и потребности в искусственной вентиляции легких, как среднюю. Недостатками являются отсутствие маскировки данных в самых крупных исследованиях, а также неоднозначность трактовки данных. Например, достоверный интервал значений обобщенного показателя эффекта не позволяет исключить вероятность крайне малого сокращения смертности. Качество фактических данных, касающихся возникновения диареи и тошноты/рвоты, расценено как низкое в связи с отсутствием маскировки данных во многих исследованиях, а также по причине того, что общее число пациентов, участвовавших в исследованиях, на основании которых получены эти данные, ниже оптимального, обеспечивающего информативность (тем не менее, достоверный интервал для обоих конечных результатов полностью лежит в области, соответствующей вреду). Настоятельная рекомендация не применять Рекомендуется не применять гидроксихлорохин или хлорохин (настоятельная рекомендация не применять). Примечание. Эта рекомендация относится к пациентам с любой тяжестью заболевания и любой продолжительностью проявления симптоматики. 104 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Убедительность фактических данных, касающихся всех других конечных результатов, колеблется в диапазоне от низкой до очень низкой. Основными недостатками этих данных являются неоднозначность их трактовки (достоверные интервалы перекрывают как область, соответствующую важным преимуществам, так и область, соответствующую серьезному вреду), а также риск систематической ошибки (отсутствие маскировки данных). Ценностные ориентиры и предпочтения Опираясь на согласованный перечень ценностных ориентиров и предпочтений (см. раздел 7), группа по разработке руководящих принципов предположила, что, с учетом информации о вероятном отсутствии влияния гидроксихлорохина на показатель смертности или потребность в искусственной вентиляции легких при одновременном наличии риска возникновения нежелательных явлений, в том числе диареи и тошноты и рвоты, практически все надлежащим образом информированные пациенты откажутся от применения гидроксихлорохина. По мнению экспертной группы, различия ценностных ориентиров и предпочтений, касающихся данного вмешательства, у разных пациентов будут незначительными. Ресурсная оснащенность и другие аспекты В сравнении с другими препаратами, применяемыми для лечения COVID-19, гидроксихлорохин и хлорохин являются сравнительно недорогими средствами, которые в настоящее время широко доступны, в том числе в условиях низкого уровня дохода. Тем не менее экспертная группа считает, что почти все пациенты предпочтут воздержаться от применения гидроксихлорохина или хлорохина, так как вред, связанный с их использованием, превосходит преимущества. Хотя стоимость в пересчете на одного пациента может быть невысокой, группа по разработке руководящих принципов выразила обеспокоенность в связи с риском отвлечения усилий и ресурсов от мероприятий, которые с высокой вероятностью могут принести пользу, таких как применение кортикостероидов для лечения пациентов с тяжелым течением COVID-19 и другие меры поддерживающего ухода. Обоснование При вынесении настоятельной рекомендации не использовать гидроксихлорохин или хлорохин для лечения пациентов с COVID-19 экспертная группа указала на наличие фактических данных средней степени убедительности, свидетельствующих о возможном отсутствии сокращения смертности или снижения потребности в искусственной вентиляции легких на фоне приема этих средств. Кроме того, экспертной группой отмечено наличие фактических данных, указывающих на возможные отрицательные эффекты лечения, которые проявляются частой тошнотой и диареей. Экспертная группа предположила, что значимых различий ценностных ориентиров и предпочтений пациентов, а также других ситуационных факторов, например наличие ресурсов, доступность, практическая осуществимость и равноправие в области здравоохранения, выявлено не будет (см. раздел, посвященный фактическим сведениям, лежащим в основе данного решения). Анализ в подгруппах Экспертной группой не было выявлено фактических данных, которые бы свидетельствовали о различном эффекте в подгруппах пациентов с различной тяжестью заболевания, подгруппах взрослых и пожилых, а также в подгруппах, получающих препарат в различной дозировке, в связи с чем рекомендаций для подгрупп по применению данного препарата сделано не было. Иными словами, данная настоятельная рекомендация применима к пациентам с различной тяжестью заболевания, к лицам из различных возрастных групп, к лицам, получающим гидроксихлорохин в любых дозировках и по любой схеме. В указанные исследования были включены пациенты из различных стран мира, с различной тяжестью заболевания, а также получающие лечение в различных условиях (амбулаторно либо в стационаре). Несмотря на то, что в указанных исследованиях не было выявлено дополнительного эффекта в подгруппах лиц с различными сроками появления симптомов заболевания, набор во многие из исследований проводился на ранних стадиях заболевания. Таким образом, по мнению группы по разработке руководящих принципов, фактические данные применимы ко всем пациентам с COVID-19. Возможность применения Отдельные группы населения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Тем не менее экспертная группа не имела оснований предполагать, что ответ на лечение гидроксихлорохином у детей будет отличаться. Подобные соображения относятся и к беременным женщинам: не имеется данных, непосредственно характеризующих данную популяцию, с другой стороны, не имеется оснований предполагать иной ответ на лечение по сравнению с остальными взрослыми пациентами. Гидроксихлорохин проникает через плацентарный барьер и, как полагают, может приводить к поражению сетчатки у новорожденных. Хотя имеется опыт применения гидроксихлорохина у беременных женщин, страдающих системными аутоиммунными заболеваниями, такими как системная красная волчанка, они, в силу большего числа причин, чем у других пациентов, могут отказываться от применения гидроксихлорохина при COVID-19. Применение в сочетании с азитромицином В ходе СМА не было выявлено фактических данных о способности азитромицина приводить к модификации эффекта гидроксихлорохина в отношении какого‑либо конечного результата. В исследованиях не было получено данных, которые бы указывали на способность азитромицина усиливать полезные эффекты гидроксихлорохина, в связи с чем рекомендация не применять гидроксихлорохин или хлорохин не зависит от одновременного приема пациентами азитромицина. Малоизученные вопросы Перечень актуальных малоизученных вопросов представлен в конце документа (раздел 9). Группа по разработке руководящих принципов сочла маловероятной возможность выявления в ходе дальнейших исследований подгруппы пациентов, которые могут получить пользу от приема гидроксихлорохина или хлорохина. 105 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с COVID-19 (любая тяжесть заболевания) Вмешательство: гидроксихлорохин Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных по гидроксихлорохину использовались ОДСМА 30 РКИ с участием 10 921 пациента, на основании чего были получены относительные оценки влияния на важные для пациентов результаты (таблица). В пяти исследованиях (всего 414 участников) ряд пациентов был рандомизирован в группу лечения хлорохином. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения гидроксихлорохина для лечения пациентов с COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах В ходе оценки данных по гидроксихлорохину группа по разработке руководящих принципов запросила проведение анализа в подгруппах на основании возраста (сравнение групп детей, лиц молодого возраста [например, до 70 лет] и пожилых [например, ≥70 лет]), тяжести заболевания (нетяжелое, тяжелое, крайне тяжелое течение COVID-19) и одновременного применения азитромицина. Кроме того, экспертная группа запросила выполнение анализа в подгруппах пациентов, выделенных по критерию лечения гидроксихлорохином в высокой и низкой дозировке. Ввиду использования в ходе испытаний различных нагрузочных и поддерживающих доз, а также разной длительности лечения, выделение категорий по критерию дозировки гидроксихлорохина не было возможным. В связи с этим при содействии специалиста в области фармакологии (профессор Эндрю Оуэн) была составлена модель зависимости расчетной концентрации препарата в сыворотке крови от времени. Согласно гипотезе, при достижении высоких значений минимальной концентрации препарата в начале периода лечения (например, концентрация на третий день) эффект может быть выше, чем при достижении низких значений минимальной концентрации. Кроме того, согласно гипотезе, более высокие концентрации препарата в сыворотке (например, пиковая концентрация в заключительный день лечения) могут создавать, в отличие от более низких концентраций, крайне высокий риск возникновения нежелательных эффектов. В рамках полученной фармакокинетической модели наблюдалась высокая степень корреляции кумулятивной дозы со всеми показателями сывороточной концентрации препарата на третий, а также в заключительный день лечения, в связи с чем принято решение использовать кумулятивную дозу в качестве основного аналитического показателя. Минимальная концентрация препарата на третий день в наименьшей степени коррелировала с общей кумулятивной дозой (R2 = 0,376), в связи с чем был выполнен анализ чувствительности в подгруппах с использованием расчетной величины минимальной концентрации препарата на третий день в качестве критерия эффективности. Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство гидроксихлорохин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 1,11 (95% ДИ: 0,95–1,31) На основании данных по 10 859 пациентам в 29 исследованиях1 (рандомизированные контролируемые) 106 на 1000 116 на 1000 Средняя Ввиду пограничной вероятности систематической ошибки и неоднозначности трактовки данных2 Предположительно, применение гидроксихлорохина не приводит к сокращению показателя смертности. Разница: увеличение на 10 случаев на 1000 (95% ДИ: сокращение на 5 случаев – увеличение на 28 случаев) Искусственная вентиляция легких Отношение шансов: 1,2 (95% ДИ: 0,83–1,81) На основании данных по 6379 пациентам в 5 исследованиях (рандомизированные контролируемые) 105 на 1000 123 на 1000 Средняя Ввиду пограничной вероятности систематической ошибки и существенной неоднозначности трактовки данных3 Применение гидроксихлорохина предположительно не приводит к снижению потребности в искусственной вентиляции легких. Разница: увеличение на 18 случаев на 1000 (95% ДИ: сокращение на 16 случаев – увеличение на 70 случаев) 106 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство гидроксихлорохин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Элиминация вируса 7 дней Отношение шансов: 1,08 (95% ДИ: 0,25–4,78) На основании данных по 280 пациентам в 4 исследованиях4 (рандомизированные контролируемые) 483 на 1000 502 на 1000 Крайне низкая Ввиду крайней неоднозначности трактовки данных5 Влияние гидроксихлорохина на элиминацию вируса остается крайне неопределенным. Разница: увеличение на 19 случаев на 1000 (95% ДИ: сокращение на 294 случая – увеличение на 334 случая) Госпитализация Отношение шансов: 0,39 (95% ДИ: 0,12–1,28) Данные по 465 пациентам, полученные в 1 исследовании. (рандомизированные контролируемые) 47 на 1000 19 на 1000 Крайне низкая Ввиду крайне косвенного характера данных и существенной неоднозначности их трактовки6 Влияние гидроксихлорохина на потребность в госпитализации не определено. Разница: сокращение на 28 случаев на 1000 (95% ДИ: сокращение на 41 случай – увеличение на 12 случаев) Кардиотоксичность На основании данных по 3287 пациентам в 7 исследованиях (рандомизированные контролируемые) 46 на 1000 56 на 1000 Крайне низкая Ввиду существенной неоднозначности трактовки данных, вероятности систематической ошибки и косвенного характера данных7 Влияние гидроксихлорохина на развитие кардиотоксичности не определено. Разница: увеличение на 10 случаев на 1000 (95% ДИ: увеличение на 0 случаев – увеличение на 30 случаев) Диарея Отношение шансов: 1,95 (95% ДИ: 1,4–2,73) На основании данных по 979 пациентам в 6 исследованиях (рандомизированные контролируемые) 149 на 1000 255 на 1000 Низкая Ввиду существенной неоднозначности трактовки данных и риска систематической ошибки8 Применение гидроксихлорохина может приводить к увеличению риска возникновения диареи. Разница: увеличение на 106 случаев на 1000 (95% ДИ: увеличение на 48 случаев – увеличение на 174 случая) Тошнота/рвота Отношение шансов: 1,74 (95% ДИ: 1,26–2,41) На основании данных по 1429 пациентам в 7 исследованиях (рандомизированные контролируемые) 99 на 1000 161 на 1000 Низкая Ввиду существенной неоднозначности трактовки данных и высокого риска систематической ошибки9 Применение гидроксихлорохина может приводить к увеличению риска возникновения тошноты и рвоты. Разница: увеличение на 62 случая на 1000 (95% ДИ: увеличение на 23 случая – увеличение на 110 случаев) Делирий Отношение шансов: 1,59 (95% ДИ: 0,77–3,28) Данные по 423 пациентам, полученные в 1 исследовании (рандомизированные контролируемые) 62 на 1000 95 на 1000 Крайне низкая Ввиду крайне косвенного характера данных и существенной неоднозначности их трактовки10 Влияние гидроксихлорохина на делирий не определено. Разница: увеличение на 33 случая на 1000 (95% ДИ: сокращение на 14 случаев – увеличение на 116 случаев) Время до клинического улучшения состояния Меньший показатель предпочтителен На основании данных по: 479 участникам в 5 исследованиях (рандомизированные контролируемые) 11 дней (среднее значение) 9 дней (среднее значение) Крайне низкая Ввиду высокой вероятности систематической ошибки, неоднозначности трактовки и косвенного характера данных11 Влияние приема гидроксихлорохина на время до клинического улучшения состояния пациентов не определено. Разница: СО: сокращение на 2 (95% ДИ: сокращение на 4 случая – увеличение на 0,1 случая) 107 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство гидроксихлорохин Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 5534 участникам в 5 исследованиях (рандомизированные контролируемые) 12,8 дня (среднее значение) 12,9 дня (среднее значение) Низкая Ввиду существенной неоднозначности трактовки данных и высокого риска систематической ошибки12 Применение гидроксихлорохина может не оказывать влияния на продолжительность госпитализации. Разница: СО: увеличение на 0,1 (95% ДИ: сокращение на 1,9 случая – увеличение на 2 случая) Время до элиминации вируса Меньший показатель предпочтителен На основании данных по: 440 участникам в 5 исследованиях (рандомизированные контролируемые) 9,7 дня (среднее значение) 10,6 дня (среднее значение) Крайне низкая Ввиду высокой вероятности систематической ошибки и крайней неоднозначности трактовки13 Влияние применения гидроксихлорохина на продолжительность времени до элиминации вируса не определено. Разница: СО: сокращение на 0,7 (95% ДИ: сокращение на 4,3 случая – увеличение на 4,8 случая) Нежелательные явления, приводящие к отмене препарата На основании данных по: 210 участникам в 3 исследованиях (рандомизированные контролируемые) В связи с развитием нежелательных эффектов, два из 108 пациентов, рандомизированных в группу лечения гидроксихлорохином, прекратили прием препарата. Прекращение приема препарата не было зарегистрировано ни у одного из 102 пациентов, находящихся в группе плацебо/стандартного лечения. Крайне низкая В связи с чрезвычайно высокой степенью неоднозначности трактовки данных14 Влияние гидроксихлорохина на развитие нежелательных явлений, приводящих к отмене препарата, не определено. 1. Систематический обзор [1]. Уровень для сравнения/группа сравнения: первичное исследование. Риски летального исхода и искусственной вентиляции легких были определены на основании исследования ВОЗ SOLIDARITY для пациентов с тяжелым и крайне тяжелым течением COVID-19. 2. Неоднозначность трактовки данных: существенная. 95% ДИ накрывает область минимально значимого различия (сокращение показателя смертности на 2%). 3. Неоднозначность трактовки данных: существенная. Широкие доверительные интервалы. 4. Систематический обзор. Применялась медианная частота событий для всех пациентов, которые были рандомизированы в группу стандартного лечения во всех рассмотренных исследованиях. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [1], 5. Неоднозначность трактовки данных: крайняя. Широкие доверительные интервалы. 6. Косвенный характер данных: существенный. Неоднозначность трактовки данных: крайняя. 7. Риск систематической ошибки: существенный. Проведение исследований без маскировки – различное определение кардиотоксичности. Косвенный характер данных: существенный. Определение выраженной кардиотоксичности происходило в исследованиях различным образом. Неоднозначность трактовки данных: существенная. 8. Риск систематической ошибки: существенный. Выраженный эффект согласуется с некоторыми косвенными данными, что смягчает остроту проблемы. Неоднозначность трактовки данных: существенная. Не удовлетворены требования в отношении оптимального объема информации. Повышение ранга: существенная величина эффекта. 9. Риск систематической ошибки: существенный. Выраженный эффект согласуется с некоторыми косвенными данными, что смягчает остроту проблемы. Неоднозначность трактовки данных: существенная. Не удовлетворены требования в отношении оптимального объема информации. Повышение ранга: существенная величина эффекта. 10. Косвенный характер данных: существенный. Наступление данного исхода учитывали не во всех случаях, не было представлено определения делирия. Неоднозначность трактовки данных: крайняя. 11. Риск систематической ошибки: существенный. Косвенный характер данных: существенный. Различные определения клинического улучшения. Неоднозначность трактовки данных: существенная. 12. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: существенная. Широкие доверительные интервалы. 13. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: крайняя. 14. Неоднозначность трактовки данных: крайняя. 108 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.14. Комбинация лопинавира и ритонавира (опубликовано 17 декабря 2020 г.) Справочная информация Рекомендации в отношении комбинации лопинавира и ритонавира были опубликованы 17 декабря 2020 г. в третьей версии вариативных рекомендаций ВОЗ, а также в разделе Rapid Recommendations журнала BMJ. Документ был подготовлен в связи с выходом в свет 15 октября 2020 г. предварительной версии публикации о результатах исследования ВОЗ SOLIDARITY, в которой были описаны результаты лечения комбинацией лопинавира и ритонавира, ремдесивиром и гидроксихлорохином пациентов, госпитализированных по поводу COVID-19 (15). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся комбинации лопинавира и ритонавира, внесено не было. Госпитализированные пациенты с COVID-19, независимо от тяжести заболевания Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Группой по разработке руководящих принципов не было найдено убедительных данных, подтверждающих способность комбинации лопинавира и ритонавира приводить к улучшению показателей, которые представляют важность для пациентов, например к сокращению смертности, потребности в искусственной вентиляции легких, времени до клинического улучшения состояния и другим. В части показателей смертности и потребности в искусственной вентиляции легких указанное решение основано на фактических данных средней степени убедительности; в части остальных конечных результатов – на данных низкой или крайне низкой степени убедительности. Имеются данные, которые с низкой степенью убедительности указывают на то, что применение комбинации лопинавира и ритонавира может приводить к увеличению риска возникновения диареи, а также тошноты и рвоты, что согласуется с косвенными данными о применении данной комбинации у пациентов с ВИЧ. Диарея и рвота могут повышать риск развития гиповолемии, гипотонии и острого повреждения почек, особенно в условиях ограниченности ресурсов здравоохранения. Определенность эффекта препарата в отношении элиминации вируса и возникновения острого повреждения почек была низкой. По данным анализа, в подгруппах модификации эффекта в зависимости от тяжести заболевания (сравнение лиц с крайне тяжелым и тяжелым/нетяжелым течением заболевания либо с нетяжелым и крайне тяжелым/тяжелым течением заболевания) или возраста (сравнение лиц в возрасте до 70 лет с лицами в возрасте ≥70 лет) не наблюдалось. В связи с отсутствием данных, свидетельствующих о статистическом эффекте в подгруппах, формальная оценка при помощи инструмента ICEMAN не проводилась. Убедительность фактических данных Фактические данные получены по итогам систематического обзора и СМА семи РКИ, в которых отражены данные в общей сложности о 7429 пациентах, госпитализированных по поводу COVID-19 различной тяжести, а также различные данные о конечных результатах, представляющих интерес для экспертной группы по разработке руководящих принципов (1). По мнению экспертной группы, степень убедительности данных в отношении показателя смертности, а также потребности в искусственной вентиляции легких была средней, в отношении диареи, тошноты и длительности госпитализации – низкой, а в отношении влияния препарата на элиминацию вируса, острое повреждение почек и времени до клинического улучшения состояния пациентов – крайне низкой. В связи с риском систематической ошибки и неоднозначностью трактовки данных (широкие доверительные интервалы, не позволяющие исключить как важных преимуществ, так и вреда) экспертная группа снизила свою оценку влияния препарата на возможность достижения большинства конечных результатов. Ценностные ориентиры и предпочтения Опираясь на согласованный перечень ценностных ориентиров и предпочтений (см. раздел 7), группа по разработке руководящих принципов предположила, что с учетом информации о вероятном отсутствии влияния комбинации лопинавира и ритонавира на показатель смертности или потребность в искусственной вентиляции легких при одновременном наличии риска возникновения нежелательных явлений, в том числе диареи, а также тошноты и рвоты, практически все надлежащим образом информированные пациенты откажутся от применения этой комбинации. По мнению экспертной группы, различия ценностных ориентиров и предпочтений, касающихся данного вмешательства, у разных пациентов будут незначительными. Настоятельная рекомендация не применять Рекомендуется не применять комбинацию лопинавира и ритонавира (настоятельная рекомендация не применять). Примечание. Эта рекомендация относится к пациентам с любой тяжестью заболевания и любой продолжительностью проявления симптоматики. 109 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Ресурсная оснащенность и другие аспекты Хотя стоимость комбинированного препарата лопинавира и ритонавира ниже по сравнению с другими изучаемыми препаратами для лечения COVID‑19, и он, как правило, доступен в большинстве лечебно‑профилактических учреждений, группа по разработке руководящих принципов выразила обеспокоенность в связи с издержками альтернативных возможностей и подчеркнула необходимость продолжения работы и дальнейшего направления ресурсов на имеющиеся оптимальные схемы поддерживающего лечения или применение кортикостероидов у пациентов с тяжелым течением COVID-19. Обоснование При вынесении на основании фактических данных настоятельной рекомендации не использовать комбинацию лопинавира и ритонавира для лечения пациентов с COVID-19 экспертная группа указала на наличие фактических данных средней степени убедительности, свидетельствующих о возможном отсутствии сокращения смертности или снижения потребности в искусственной вентиляции легких на фоне приема этих средств. Кроме того, экспертной группой отмечено наличие фактических данных, указывающих на возможные отрицательные эффекты лечения, которые проявляются частой тошнотой и диареей. Экспертная группа предположила, что различия ценностных ориентиров и предпочтений пациентов, а также другие ситуационные факторы, например наличие ресурсов, доступность, практическая осуществимость и равноправие в области здравоохранения, не будут значимыми и не приведут к изменению рекомендации (см. краткое изложение данных фактов в разделе «Фактические сведения, лежащие в основе данной рекомендации). Анализ в подгруппах Экспертной группой не было выявлено фактических данных, которые бы свидетельствовали о различном эффекте в подгруппах пациентов с различной тяжестью заболевания, подгруппах взрослых и пожилых, в связи с чем рекомендаций для подгрупп по применению данного препарата сделано не было. Несмотря на то, что в указанных исследованиях не было выявлено дополнительного эффекта в подгруппах лиц с различными сроками появления симптомов заболевания, набор во многие из исследований проводился на ранних стадиях заболевания. Настоятельная рекомендация применима к пациентам с различной тяжестью заболевания и к лицам из различных возрастных групп. Возможность применения Ни в одном из рассмотренных РКИ не участвовали дети, в этой связи применимость данной рекомендации к детям остается невыясненной. Тем не менее, экспертная группа не имела оснований предполагать, что ответ на лечение комбинацией лопинавира и ритонавира у детей будет отличаться. Подобные соображения относятся и к беременным женщинам: не имеется данных, непосредственно характеризующих данную популяцию, с другой стороны, не имеется оснований предполагать иной ответ на лечение по сравнению с остальными взрослыми пациентами. Как правило, у пациентов, получающих комбинацию лопинавира и ритонавира в связи с ВИЧ-инфекцией, данный курс продолжают на фоне лечения COVID-19. Малоизученные вопросы Перечень актуальных малоизученных вопросов представлен в конце документа (раздел 9). Группа по разработке руководящих принципов сочла маловероятной возможность выявления в ходе дальнейших исследований подгруппы пациентов, которые могут получить пользу от приема комбинации лопинавира и ритонавира. Другие соображения Применение комбинации лопинавира и ритонавира у пациентов, имеющих недиагностированную ВИЧ‑инфекцию, либо не получающих лечение по поводу ВИЧ‑инфекции может спровоцировать развитие устойчивости вируса к важным противовирусным препаратам. Масштабное применение комбинации лопинавира и ритонавира для лечения COVID-19 может привести к дефициту препаратов для лиц, живущих с ВИЧ. 110 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с COVID-19 (любая тяжесть заболевания) Вмешательство: комбинация лопинавира и ритонавира Сравнение: стандарт оказания помощи Резюме Резюме фактических данных При составлении резюме фактических данных по комбинации лопинавира и ритонавира использовались ОДСМА семи РКИ с участием 7429 пациентов. Примечание: ни в одном из указанных исследований не участвовали дети или подростки в возрасте младше 19 лет (таблица). В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения комбинации лопинавира и ритонавира для лечения пациентов с COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Анализ в подгруппах Группа по разработке руководящих принципов запросила проведение анализа в подгруппах на основании возраста (сравнение групп детей и взрослых [например, до 70 лет], а также пожилых [например, от 70 лет или старше]) и тяжести заболевания (нетяжелое, тяжелое, крайне тяжелое течение COVID-19). Группа по разработке руководящих принципов рассмотрела другие потенциально важные подгруппы пациентов, в том числе выделяемые по критериям длительности периода от появления симптомов заболевания до начала лечения, а также лекарственных назначений, однако пришла к выводу о том, что без доступа к сведениям о конкретных участниках и/или более подробных сведений о конкретных испытаниях анализ этой информации невозможен. Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство комбинация лопинавира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность Отношение шансов: 1 (95% ДИ: 0,82–1,2) На основании данных по 8061 пациентам в 4 исследованиях1 (рандомизированные контролируемые) 106 на 1000 106 на 1000 Средняя Ввиду пограничной вероятности систематической ошибки и неоднозначности трактовки данных 2 Предположительно, применение комбинации лопинавира и ритонавира не оказывает влияние на показатель смертности. Разница: сокращение на 0 случаев на 1000 (95% ДИ: сокращение на 17 случаев – увеличение на 19 случаев) Искусственная вентиляция легких Относительный риск 1,16 (95% ДИ 0,98– 1,36) на основании данных о 7579 участниках в 3 исследованиях (рандомизированные контролируемые) 105 на 1000 122 на 1000 Средняя Ввиду пограничной вероятности систематической ошибки и неоднозначности трактовки данных3 По‑видимому, применение комбинации лопинавира и ритонавира не приводит к снижению потребности в искусственной вентиляции легких. Разница: увеличение на 17 случаев на 1000 (ДИ 95% сокращение на 2 случая – увеличение на 38 случаев) Элиминация вируса Отношение шансов: 0,35 (95% ДИ 0,04–1,97) на основании данных о 171 участнике в 2 исследованиях4 (рандомизированные контролируемые) 483 на 1000 246 на 1000 Низкая Ввиду крайней неоднозначности трактовки данных5 Влияние комбинации лопинавира и ритонавира на элиминацию вируса остается крайне неопределенным. Разница: сокращение на 237 случаев на 1000 (95% ДИ: сокращение на 447 случаев – увеличение на 165 случаев) Острое повреждение почек Относительный риск: на основании данных по 259 пациентам в 2 исследованиях. (рандомизированные контролируемые) 45 на 1000 25 на 1000 Крайне низкая Ввиду высокой вероятности систематической ошибки и крайней неоднозначности трактовки6 Влияние комбинации лопинавира и ритонавира на возникновение острого повреждения почек практически невозможно определить. Разница: сокращение на 20 случаев на 1000 (95% ДИ: сокращение на 70 случаев – увеличение на 20 случаев) 111 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство комбинация лопинавира и ритонавира Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Диарея Отношение шансов: 4,28 (95% ДИ: 1,99–9,18) На основании данных по 370 пациентам в 4 исследованиях (рандомизированные контролируемые) 67 на 1000 235 на 1000 Средняя В связи с высоким риском систематической ошибки и неоднозначностью трактовки данных; ранг повышен ввиду большой величины эффекта7 Применение комбинации лопинавира и ритонавира может приводить к увеличению риска возникновения диареи. Разница: на 168 больше на 1000 (ДИ 95% на 58 больше – на 330 больше) Тошнота/рвота Относительный риск: на основании данных по 370 пациентам в 4 исследованиях. (рандомизированные контролируемые) 17 на 1000 177 на 1000 Средняя Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки8 Применение комбинации лопинавира и ритонавира может приводить к увеличению риска возникновения тошноты/рвоты. Разница: на 160 больше на 1000 (ДИ 95% на 100 больше – на 210 больше) Время до клинического улучшения состояния Меньший показатель предпочтителен На основании данных по: 199 участникам в 1 исследовании (рандомизированные контролируемые) 11 дней (среднее значение) 10 дней (среднее значение) Крайне низкая Ввиду высокой вероятности систематической ошибки и крайней неоднозначности трактовки9 Влияние применения комбинации лопинавира и ритонавира на время до клинического улучшения состояния пациентов остается крайне неопределенным. Разница: СО: на 1 меньше (95% ДИ: на 4,1 дня меньше – на 3,2 дня больше) Продолжительность госпитализации Меньший показатель предпочтителен На основании данных по: 5239 участникам в 2 исследованиях (рандомизированные контролируемые) 12,8 дня (среднее значение) 12,5 дня (среднее значение) Низкая Ввиду высокой вероятности систематической ошибки и неоднозначности трактовки10 Применение комбинации лопинавира и ритонавира может не оказывать влияния на продолжительность госпитализации. Разница: СР на 0,3 меньше (95% ДИ: меньше на 3 дня – больше на 2,5 дня) 1. Систематический обзор. Уровень для сравнения/группа сравнения: первичное исследование [15]. Риски летального исхода и искусственной вентиляции легких были определены на основании исследования ВОЗ SOLIDARITY для пациентов с тяжелым и крайне тяжелым течением COVID-19. Справочные материалы: [1], 2. Неоднозначность трактовки данных: существенная. 95% ДИ накрывает область минимально значимого различия (сокращение показателя смертности на 2%). 3. Неоднозначность трактовки данных: существенная. Широкие доверительные интервалы. 4. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Применялась медианная частота событий для всех пациентов, которые были рандомизированы в группу стандартного лечения во всех рассмотренных исследованиях. Справочные материалы: [1], 5. Неоднозначность трактовки данных: крайняя. Широкие доверительные интервалы. 6. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: крайняя. Широкие доверительные интервалы. 7. Риск систематической ошибки: существенный. Выраженный эффект согласуется с некоторыми косвенными данными, что смягчает остроту проблемы. Неоднозначность трактовки данных: существенная. Небольшое количество пациентов и событий. Повышение ранга: существенная величина эффекта. 8. Риск систематической ошибки: существенный. Выраженный эффект согласуется с некоторыми косвенными данными, что смягчает остроту проблемы. Неоднозначность трактовки данных: существенная. Небольшое количество пациентов и событий. Повышение ранга: существенная величина эффекта. 9. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: крайняя. Широкие доверительные интервалы, небольшое количество пациентов. 10. Риск систематической ошибки: существенный. Неоднозначность трактовки данных: существенная. Широкие доверительные интервалы. 112 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 6.15. Системные кортикостероиды (опубликовано 2 сентября 2020 г.) Справочная информация Представленные ниже рекомендации в отношении использования кортикостероидов были впервые опубликованы в вариативных рекомендациях ВОЗ 2 сентября 2020 г., а также в журнале BMJ (BMJ Rapid Recommendations) 5 сентября 2020 г. Этот рекомендательный документ был подготовлен в связи с выходом в свет предварительных данных исследования RECOVERY, позднее опубликованных в виде рецензированной научной работы (14). В одиннадцатой версии документа (данное издание) изменений в рекомендации, касающиеся кортикостероидов, внесено не было. Хотя рекомендации остаются неизменными, резюме фактических данных в отношении кортикостероидов у пациентов с COVID-19 было обновлено перед выходом в свет шестой версии вариативных рекомендаций. В настоящее время основой для определения величины показателя смертности в исходный момент времени служит исследование ВОЗ SOLIDARITY (так же, как и для других препаратов, указанных в данных рекомендациях) (15), а не изначально применявшееся когортное исследование ISARIC (149), в котором риск смертности в глобальном масштабе, по-видимому, завышен. Кроме того, необходимость данного обновления объясняется потребностью в определении величины исходного риска смертности в резюме фактических данных, служащих для обоснования настоятельной рекомендации использовать блокаторы рецепторов к IL-6 в целях лечения пациентов с тяжелой формой COVID-19 наряду со стандартом оказания помощи, назначение кортикостероидов в рамках которого обеспечивает относительное снижение смертности на 21%. Для пациентов с тяжелым и крайне тяжелым течением COVID-19 Практические сведения Способ введения. Системные кортикостероиды могут назначаться как для приема внутрь, так и для внутривенного введения. Необходимо заметить, что, несмотря на чрезвычайно высокую биодоступность дексаметазона (то есть концентрации в плазме крови после приема внутрь или внутривенного введения сопоставимы), у пациентов с крайне тяжелым течением заболевания ввиду нарушения функции кишечника всасывание питательных веществ или лекарственных средств может быть нарушено. Таким образом, при подозрении на дисфункцию кишечника у пациента клиницист может рассмотреть возможность внутривенного, а не перорального введения кортикостероидов. Продолжительность. Большинство пациентов получали дексаметазон в дозировке 6 мг в день на протяжении 10 дней, тем не менее, общая продолжительность схем лечения в семи рассмотренных исследованиях находилась в диапазоне от 5 до 14 дней, и на момент выписки из стационара оно, как правило, завершалось (то есть фактическая продолжительность лечения могла быть меньше, чем указанная в протоколах). Дозировка. Использование дексаметазона в лекарственной форме для приема один раз в день может способствовать более тщательному соблюдению режима лечения. Дексаметазон в дозировке 6 мг эквивалентен (по глюкокортикоидному действию) 150 мг гидрокортизона (например, 50 мг каждые 8 часов), 40 мг преднизона или 32 мг метилпреднизолона (например, 8 мг каждые 6 часов или 16 мг каждые 12 часов). Наблюдение. Целесообразно проведение мониторинга уровня глюкозы у пациентов с тяжелым и крайне тяжелым течением COVID‑19 независимо от анамнеза диабета. Временные рамки. Вопрос продолжительности лечения от момента дебюта симптомов стал для группы дискуссионным. В исследовании RECOVERY сообщается о результатах анализа данных в подгруппах, согласно которому начало лечения через 7 и более дней после возникновения симптомов заболевания может быть более предпочтительным, чем лечение в период до 7 дней от момента появления симптомов. Данные post hoc анализа в подгруппах, проведенного в рамках проспективного метаанализа, не подтвердили эту гипотезу. По мнению ряда членов экспертной группы, переход к системному лечению кортикостероидами после развития иммунной реакции на репликацию вируса представляется оправданным, тем не менее многие отметили, что момент дебюта симптомов зачастую невозможно достоверно установить на практике, а признаки тяжести заболевания нередко проявляются достаточно поздно (то есть свидетельствуют о колинейности тяжести заболевания и его продолжительности). Экспертная группа пришла к выводу о том, что имеющиеся фактические данные свидетельствуют о необходимости склоняться в пользу применения кортикостероидов при лечении пациентов с тяжелым или крайне тяжелым течением COVID‑19 (даже в том случае, если от момента появления симптомов прошло менее 7 дней) и склоняться в пользу отказа от применения кортикостероидов при лечении пациентов, не имеющих тяжелой формы заболевания (даже в том случае, если от момента появления симптомов прошло более 7 дней). Настоятельная рекомендация в пользу применения Новые сведения Рекомендуется лечение с использованием системных кортикостероидов (настоятельная рекомендация в пользу применения). 113 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред По мнению членов экспертной группы, проголосовавших за вынесение условной рекомендации, информация о потенциальном вреде, связанном с системным применением кортикостероидов для лечения COVID‑19, в соответствующих исследованиях представлена недостаточно. В период между двумя заседаниями экспертной группы таблица резюме наблюдений была дополнена косвенными данными, относящимися к потенциальным отрицательным эффектам системной терапии стероидами и полученными в исследованиях сепсиса, ОРДС, а также внебольничной пневмонии(150)(151). В целом эти данные характеризуются низкой степенью убедительности, тем не менее они внушают определенный оптимизм и свидетельствуют о том, что прием кортикостероидов не был связан с дополнительным риском нежелательных явлений, за исключением возможного увеличения частоты гипергликемии (средняя степень убедительности данных, величина абсолютного эффекта: увеличение частоты на 46 случаев на 1000 пациентов, 95% ДИ в диапазоне от увеличения на 23 случая до увеличения на 72 случая) и гипернатриемии (средняя степень убедительности данных, увеличение частоты на 26 случаев на 1000 пациентов, 95% ДИ в диапазоне от увеличения на 13 случаев до увеличения на 41 случай). Кроме того, члены экспертной группы отметили, что с учетом ожидаемого влияния приема кортикостероидов на смертность, большинство пациентов не будут склонны отказываться от данного лечебного мероприятия с целью избежать неблагоприятных явлений, которые, как полагают, имеют меньшую значимость для большинства пациентов, чем летальный исход. В отличие от новых средств, предлагаемых для лечения COVID‑19, кортикостероиды для системного применения хорошо знакомы клиницистам по практической работе, и члены экспертной группы выразили уверенность в их общем профиле безопасности. Кроме того, члены экспертной группы выразили уверенность в том, что клиницистам, применяющим данный рекомендательный документ, будут известны другие возможные побочные эффекты и противопоказания для системной терапии кортикостероидами, которые могут различаться в зависимости от географической локализации и определяться эндемичной микрофлорой. Тем не менее клиницисты должны с осторожностью подходить к применению кортикостероидов у пациентов с диабетом или ослабленным иммунитетом. Помимо этого, экспертная группа вынесла данную рекомендацию на основании фактических данных средней степени убедительности в отношении сокращения 28‑дневной смертности на 8,7% у пациентов с крайне тяжелым и на 6,7% у пациентов с тяжелым течением COVID‑19, не находившихся в крайне тяжелом состоянии соответственно. В пятой версии данных вариативных рекомендаций оценочная величина риска в исходный момент времени была уточнена на основании данных исследования ВОЗ SOLIDARITY, которое, как представляется, является наилучшим источником прогностических данных в странах, столкнувшихся с пандемией COVID-19. В целом отмечается сокращение 28-дневной смертности на 3,3% в группе пациентов с тяжелым или крайне тяжелым течением COVID-19; степень убедительности данных по-прежнему считается средней, комиссия полагает, что данные свидетельствуют об очевидных преимуществах для пациентов и не влекут необходимости изменения рекомендаций. Ценностные ориентиры и предпочтения Экспертная группа изучила поставленные перед ней вопросы с точки зрения ценностных ориентиров и предпочтений пациентов, однако в свете того, что пандемия ложится тяжким бременем на системы здравоохранения во всем мире, также уделила значительное внимание ресурсной обеспеченности и равноправному доступу. Работа строилась в предположении о том, что решающее значение для пациентов имеет сокращение смертности в связи с приемом кортикостероидов, а также о том, что не следует ожидать различия предпочтений, в том числе существенного, в отношении возможных вариантов лечения при тяжелом течении COVID-19. Ресурсная оснащенность и другие аспекты Необходимость в ресурсной оснащенности, практическая осуществимость, обеспечение равноправия и соблюдения прав человека При составлении этого рекомендательного документа экспертной группой рассмотрение изучаемых проблем происходило с точки зрения пациента, однако не меньшее внимание было уделено распределению ресурсов. При таком подходе в центре внимания находились издержки альтернативных возможностей, связанные со значительным масштабом оказания помощи в связи с COVID-19. В отличие от других изучаемых лекарственных средств для лечения COVID‑19, которые, как правило, дороги, зачастую не лицензированы, труднодоступны и требуют наличия современной медицинской инфраструктуры, кортикостероиды для системного применения недороги, просты в применении и доступны во всем мире (152). Дексаметазон и преднизолон – одни из самых часто встречающихся препаратов в национальных перечнях основных лекарственных средств; они включены в такие перечни в 95% стран мира. Дексаметазон был впервые включен ВОЗ в перечень основных лекарственных средств в 1977 г., а преднизолон – спустя еще 2 года (153). Таким образом, применение системных кортикостероидов относится к сравнительно небольшому числу вмешательств по поводу COVID‑19, которые могут содействовать обеспечению более справедливого и равноправного доступа к здравоохранению. Сила данной рекомендации определяется перечисленными соображениями. Приемлемость Принимая во внимание простоту применения, относительно короткую продолжительность курса системной терапии кортикостероидами, а также в целом удовлетворительный профиль безопасности кортикостероидов для системного применения при их использовании в течение 7–10 дней, экспертная группа пришла к заключению о том, что степень приемлемости данного мероприятия высока. 114 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Обоснование Данная рекомендация была сделана после того, как на голосование был вынесен вопрос о степени убедительности рекомендации в пользу системного применения кортикостероидов. Из 23 членов экспертной группы, имеющих право голоса, 19 (83%) проголосовали в пользу настоятельной рекомендации и 4 (17%) – в пользу условной рекомендации. Ниже кратко изложено обоснование осторожной позиции, которой придерживались четверо членов экспертной группы и которую разделяли некоторые другие члены, проголосовавшие за вынесение настоятельной рекомендации. Возможность применения По мнению членов экспертной группы, проголосовавших за вынесение условной рекомендации, многие пациенты, которые могли удовлетворить критериям включения в исследование RECOVERY, не были допущены лечащими врачами к участию в испытании эффектов кортикостероидов, и вынесение настоятельной рекомендации, по их мнению, невозможно в отсутствие подробной характеристики исключенных пациентов. По мнению других членов экспертной группы, такая доля пациентов, исключенных из исследования, представляет собой норму для испытаний в условиях реальной клинической практики, а основной причиной для отказа в участии в исследовании (хотя сбор подробных сведений о причинах исключения не проводился), по‑видимому, явилась опасность отмены кортикостероидов у пациентов, имеющих явные показания для их назначения (подтверждено в неформальной беседе с ведущим исследователем испытания RECOVERY). Члены экспертной группы отметили, что для курса лечения кортикостероидами продолжительностью 7–10 дней имеется крайне небольшое число абсолютных противопоказаний, рекомендации ориентированы на среднестатистическую популяцию пациентов, и, очевидно, в случае если лечащий врач считает, что данное лечебное мероприятие противопоказано для конкретного пациента, соответствующие рекомендации не должны применяться даже при их настоятельном характере. Кроме того, экспертная группа пришла к выводу, что действие данной рекомендации распространяется на пациентов с тяжелым и крайне тяжелым течением COVID‑19, независимо от их нахождения на стационарном лечении. Экспертная группа исходила из предположения о том, что пациенты, относящиеся к данной группе, будут проходить лечение на базе стационара и получать респираторную поддержку в виде оксигенации либо инвазивной или неинвазивной вентиляции легких при доступности этих видов помощи. Руководствуясь при вынесении настоятельной рекомендации положениями методологии GRADE, экспертная группа исходила из допущения о том, что после полноценного информирования все или почти все пациенты с тяжелым течением COVID‑19 согласятся получать лечение кортикостероидами для системного применения. Очевидно, данное лечебное мероприятие может быть противопоказано для отдельных пациентов даже при наличии настоятельной рекомендации. Абсолютные противопоказания для проведения курса системной терапии кортикостероидами продолжительностью 7–10 дней встречаются редко. Выявляя возможные противопоказания, клиницист должен определить, лишают ли они пациента возможности получить лечение, которое может спасти жизнь. Применимость данной рекомендации недостаточно ясна в случае популяций, которые были слабо представлены в рассмотренных исследованиях, например среди детей, лиц с туберкулезом и ослабленным иммунитетом. Тем не менее клиницисты также должны выяснить, существует ли риск лишить пациента лечения, которое может спасти жизнь. С другой стороны, экспертная группа пришла к убедительному выводу о том, что данная рекомендация должна распространяться на некоторые категории пациентов, не включенные в исследование, например пациентов с тяжелым и крайне тяжелым течением COVID-19, которые не госпитализированы или не получают оксигенотерапию в связи с ограничениями ресурсного характера. Данная рекомендация не распространяется на следующие случаи применения кортикостероидов: чрескожное или ингаляционное введение, схемы лечения высокими дозами или долгосрочного лечения либо профилактический прием. Клиническая проблема/вопрос PICO Популяция: пациенты с тяжелым и крайне тяжелым течением COVID-19 (уточненная величина риска в исходный момент времени) Вмешательство: системные кортикостероиды Сравнение: стандарт оказания помощи Резюме Резюме фактических данных Работа над этим рекомендательным документом началась 22 июня 2020 г. после публикации предварительных данных исследования RECOVERY, которые к настоящему моменту имеют статус рецензированной публикации (14). Кортикостероиды входят в примерный перечень ВОЗ основных лекарственных средств, они легко доступны во всем мире по невысокой цене и представляют интерес для всех групп заинтересованных сторон. В ходе работы группа по подготовке рекомендательного документа рассмотрела данные двух метаанализов, в которых были объединены результаты восьми рандомизированных исследований (7184 участника) применения системных кортикостероидов для лечения COVID-19(1)(154). Кроме того, в основу обсуждения группы легли опубликованные данные двух других метаанализов, в которых были объединены данные о безопасности применения системных кортикостероидов в популяциях пациентов, отличных от изучаемой, но соответствующих ей по важным параметрам. 115 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения системных кортикостероидов для лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. Далее в документе представлены более подробные сведения о результатах исследований и метаанализе, а также анализе подгрупп, которые легли в основу данных рекомендаций. В разделе 7 приведены сведения об источниках оценок риска в исходный момент времени, на основе которых осуществлялся расчет величины абсолютного эффекта. Семнадцатого июля 2020 г. экспертная группа рассмотрела фактические данные, полученные в ходе восьми РКИ (7184 пациента), в которых сравнивалось применение системных кортикостероидов и стандартное лечение COVID‑19. В самом масштабном из семи исследований, RECOVERY, изучалось влияние применения дексаметазона в дозировке 6 мг один раз в день (прием внутрь либо внутривенное введение) на протяжении не более 10 дней у 6425 госпитализированных пациентов в Соединенном Королевстве (2104 были рандомизированы в группу лечения дексаметазоном и 4321 – в группу стандартного лечения), а данные о смертности были представлены в разбивке по подгруппам (тяжелое и нетяжелое течение) (14). К моменту рандомизации 16% пациентов получали респираторную поддержку методом инвазивной вентиляции легких либо находились на экстракорпоральной мембранной оксигенации; 60% находились на оксигенации (с применением неинвазивной вентиляции или без нее); 24% не получали какого‑либо из этих видов помощи. Данные семи других менее масштабных исследований охватывали 63 случая пациентов, которые не находились в крайне тяжелом состоянии, и порядка 700 пациентов, находившихся в крайне тяжелом состоянии (в разных исследованиях определение крайне тяжелого течения заболевания отличалось). Набор в последнее исследование проходил до 9 июня 2020 г., и около четырех пятых пациентов находились на инвазивной вентиляции легких; порядка половины были рандомизированы в группу лечения кортикостероидами и половина – в группу, не получавшую кортикостероидов. Имели место следующие схемы лечения кортикостероидами: метилпреднизолон 40 мг каждые 12 часов на протяжении 3 дней, затем 20 мг каждые 12 часов на протяжении 3 дней (GLUCOCOVID) (155); дексаметазон 20 мг ежедневно на протяжении 5 дней, затем 10 мг ежедневно на протяжении 5 дней (два исследования, DEXA-COVID, CoDEX)(156)(157); гидрокортизон 200 мг ежедневно в течение 4–7 дней, затем 100 мг ежедневно в течение 2–4 дней, затем 50 мг ежедневно на протяжении 2–3 дней (одно исследование, CAPE-COVID) (158); гидрокортизон 200 мг ежедневно в течение 7 дней (одно исследование, REMAP-CAP) (16); метилпреднизолон 40 мг, каждые 12 часов в течение 5 дней (одно исследование, Steroids-SARI) (159). Семь исследований проходили в пределах одной страны (Бразилия, Китай, Дания, Франция, Испания), а исследование REMAP‑CAP проводилось в международном масштабе (набор в исследование проходил в 14 странах Европы, Австралии, Канаде, Новой Зеландии, Саудовской Аравии и Соединенном Королевстве). Смертность на 28‑й день после рандомизации регистрировали во всех исследованиях, за исключением двух, в одном из которых этот показатель регистрировали по состоянию на 21‑й день и в другом – на 30‑й день. В одном из исследований (GLUCOCOVID, n=63) данные о смертности не были представлены в разбивке по подгруппам, в связи с чем экспертная группа приняла к рассмотрению только данные этого исследования, относящиеся к исходам искусственной вентиляции легких (155). Данные еще одного исследования, вышедшие в свет 12 августа 2020 г. (MetCOVID)(160), в котором была проведена рандомизация госпитализированных пациентов с подозрением на заражение вирусом SARS‑CoV‑2, были включены в опубликованные материалы проспективного метаанализа в качестве дополнения, так как исследование было зарегистрировано после выполнения поиска в регистрах клинических испытаний. В дополнении было показано, что включение этих сведений улучшает согласованность данных и не оказывает существенного влияния на результаты исследования. Анализ в подгруппах Во всех исследованиях проводилась оценка системного применения кортикостероидов только у пациентов с крайне тяжелым течением заболевания, за исключением исследования RECOVERY, в которое производился набор госпитализированных пациентов с COVID‑19. Экспертная группа рассмотрела результаты анализа данных исследования RECOVERY, полученных в подгруппах, в соответствии с которыми относительная эффективность системного применения кортикостероидов изменялась в зависимости от вида респираторной поддержки, которую получали пациенты на момент рандомизации. Исходя из одобренных экспертным сообществом критериев достоверности эффектов, наблюдаемых в подгруппах (110), экспертная группа заключила, что достоверность наблюдаемого в подгруппах эффекта была достаточной для вынесения отдельных рекомендаций в отношении случаев тяжелого и нетяжелого течения COVID-19. Тем не менее, признавая, что доступ к услугам здравоохранения во время пандемии может существенно различаться в разные периоды времени и в различных странах, комиссия приняла решение не рассматривать доступ к медицинским услугам (таким как госпитализация и дыхательная поддержка) в качестве критерия для определения популяции пациентов, на которую распространяется действие рекомендаций. Таким образом, экспертная группа связала модификацию эффекта, наблюдавшуюся в исследовании RECOVERY, с тяжестью заболевания. Кроме того, комиссия признала факт использования различных определений для характеристики тяжести заболевания и применения мер респираторной поддержки. В клинических рекомендациях ВОЗ в отношении COVID‑19, опубликованных 27 мая 2020 г. (версия 3), тяжесть заболевания COVID‑19 определяется в зависимости от клинических показателей, однако в целях обеспечения единообразия с предыдущими рекомендациями ВОЗ пороговое значение насыщения крови кислородом изменено с 94% до 90% (6). Критерии тяжести ВОЗ и три группы, выделенные по признаку тяжести заболевания, в отношении которых применимы рекомендации, представлены в разделе 5. 116 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Системные кортикостероиды Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность 28 дней Относительный риск 0,79 (95% ДИ: 0,7–0,9) На основании данных по 1703 пациентам в 7 исследованиях1 Последующее наблюдение: 28 дней. 160 на 1000 126 на 1000 Средняя Ввиду высокой вероятности систематической ошибки2 Применение системных кортикостероидов, по‑видимому, сокращает риск 28‑дневной смертности, вызванной COVID‑19, у пациентов с крайне тяжелым течением заболевания. Разница: сокращение на 34 случая на 1000 (95% ДИ: сокращение на 48 случаев – сокращение на 16 случаев) Потребность в инвазивной искусственной вентиляции легких 28 дней Относительный риск 0,74 (95% ДИ: 0,59– 0,93) На основании данных по 5481 пациентам в 2 исследованиях Последующее наблюдение: 28 дней. 116 на 1000 86 на 1000 Средняя Ввиду высокой вероятности систематической ошибки3 Применение системных кортикостероидов, по‑видимому, снижает потребность в искусственной вентиляции легких. Разница: сокращение на 30 случаев на 1000 (95% ДИ: сокращение на 48 случаев – сокращение на 8 случаев) Желудочно-кишечное кровотечение Относительный риск 1,06 (95% ДИ: 0,85– 1,33) На основании данных по 5403 пациентам в 30 исследованиях . 48 на 1000 51 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных4 Прием кортикостероидов, вероятно, не приводит к увеличению риска желудочно- кишечных кровотечений. Разница: увеличение на 3 случая на 1000 (95% ДИ: сокращение на 7 случаев – увеличение на 16 случаев) Случаи суперинфекции Относительный риск 1,01 (95% ДИ: 0,9– 1,13) На основании данных по 6027 пациентам в 32 исследованиях . 186 на 1000 188 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных5 Прием кортикостероидов может не приводить к увеличению риска суперинфекции. Разница: увеличение на 2 случая на 1000 (95% ДИ: сокращение на 19 случаев – увеличение на 24 случая) Гипергликемия Относительный риск 1,16 (95% ДИ: 1,08– 1,25) На основании данных по 8938 пациентам в 24 исследованиях . 286 на 1000 332 на 1000 Средняя Ввиду крайне косвенного характера данных6 Прием кортикостероидов предположительно приводит к повышению риска гипергликемии. Разница: увеличение на 46 случаев на 1000 (95% ДИ: увеличение на 23 случая – увеличение на 72 случая) Гипернатриемия Относительный риск 1,64 (95% ДИ: 1,32– 2,03) На основании данных по 5015 пациентам в 6 исследованиях. 40 на 1000 66 на 1000 Средняя Ввиду крайне косвенного характера данных7 Прием кортикостероидов предположительно приводит к повышению риска гипернатриемии. Разница: увеличение на 26 случаев на 1000 (95% ДИ: увеличение на 13 случаев – увеличение на 41 случай) Нейромышечные расстройства, проявляющиеся слабостью Относительный риск 1,09 (95% ДИ: 0,86– 1,39) На основании данных по 6358 пациентам в 8 исследованиях. 69 на 1000 75 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных8 Прием кортикостероидов, вероятно, не приводит к увеличению риска нейромышечных расстройств, проявляющихся слабостью. Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 10 случаев – увеличение на 27 случаев) 117 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение Стандарт оказания помощи Вмешательство Системные кортикостероиды Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Психоневротические состояния Относительный риск 0,81 (95% ДИ: 0,41– 1,63) На основании данных по 1813 пациентам в 7 исследованиях. 35 на 1000 28 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных9 Прием кортикостероидов, вероятно, не приводит к увеличению риска развития психоневротических состояний. Разница: сокращение на 7 случаев на 1000 (95% ДИ: сокращение на 21 случай – увеличение на 22 случая) Продолжительность госпитализации Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 6425 участникам в 1 исследовании 13 дней 12 дней Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных10 Применение стероидных средств, вероятно, приводит к существенному сокращению продолжительности госпитализации. 1. Систематический обзор [1]. Уровень для сравнения/группа сравнения: первичное исследование [15]. Уточненная по состоянию на май 2021 г. оценочная величина исходного риска смертности: по данным исследования ВОЗ SOLIDARITY (считается наилучшим источником), 28-дневная смертность у пациентов с тяжелым и крайне тяжелым течением заболевания составляет 14,6%. Данная оценочная величина скорригирована на 50% получавших кортикостероиды в рамках стандарта оказания помощи в исследовании SOLIDARITY. 2. Риск систематической ошибки: существенный. Отсутствие маскировки данных. 3. Риск систематической ошибки: существенный. Отсутствие маскировки данных. 4. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 5. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 6. Косвенный характер данных: существенный. 7. Косвенный характер данных: существенный. 8. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 9. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 10. Риск систематической ошибки: существенный. Отсутствие маскировки данных. Неоднозначность трактовки данных: существенная. Доверительный интервал не накрывает область, соответствующую полезному эффекту. Для пациентов с нетяжелым течением COVID-19 Практические сведения В случае если рассматривается применение кортикостероидов, невзирая на условную рекомендацию не применять кортикостероиды у пациентов с нетяжелым течением COVID‑19, следует принять во внимание следующую практические сведения. Способ введения. Системные кортикостероиды могут назначаться как для приема внутрь, так и для внутривенного введения. Необходимо заметить, что, несмотря на чрезвычайно высокую биодоступность дексаметазона (то есть концентрации в плазме крови после приема внутрь или внутривенного введения сопоставимы), у пациентов с крайне тяжелым течением заболевания ввиду нарушения функции кишечника всасывание питательных веществ или лекарственных средств может быть нарушено. Таким образом, при подозрении на дисфункцию кишечника у пациента клиницист может рассмотреть возможность внутривенного, а не перорального введения кортикостероидов. Продолжительность. Большинство пациентов получали дексаметазон в дозировке 6 мг в день на протяжении 10 дней, тем не менее общая продолжительность схем лечения в семи рассмотренных исследованиях находилась в диапазоне от 5 до 14 дней, и на момент выписки из стационара оно, как правило, завершалось (т.е. фактическая продолжительность лечения могла быть меньше, чем указанная в протоколах). Дозировка. Использование дексаметазона в лекарственной форме для приема один раз в день может способствовать более тщательному соблюдению режима лечения. Дексаметазон в дозировке 6 мг эквивалентен (по глюкокортикоидному действию) 150 мг гидрокортизона (например, 50 мг каждые 8 часов), 40 мг преднизона или 32 мг метилпреднизолона (например, 8 мг каждые 6 часов или 16 мг каждые 12 часов). Целесообразно проведение мониторинга уровня глюкозы у пациентов с тяжелым и крайне тяжелым течением COVID‑19 независимо от анамнеза диабета. Условная рекомендация не применять Применение кортикостероидов не рекомендуется (условная рекомендация не применять). 118 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Временные рамки. Вопрос продолжительности лечения от момента дебюта симптомов стал для группы дискуссионным. В исследовании RECOVERY сообщается о результатах анализа данных в подгруппах, согласно которому начало лечения через 7 и более дней после возникновения симптомов заболевания может быть более предпочтительным, чем лечение в период до 7 дней от появления симптомов. Данные post hoc анализа в подгруппах, проведенного в рамках проспективного метаанализа, не подтвердили эту гипотезу. По мнению ряда членов экспертной группы, переход к системному лечению кортикостероидами после развития иммунной реакции на репликацию вируса представляется оправданным. Тем не менее многие отметили, что момент дебюта симптомов зачастую невозможно достоверно установить на практике, а признаки тяжести заболевания нередко проявляются достаточно поздно (то есть свидетельствуют о колинейности тяжести заболевания и его продолжительности). Экспертная группа пришла к выводу о том, что имеющиеся фактические данные свидетельствуют о необходимости склоняться в пользу применения кортикостероидов при лечении пациентов с тяжелым или крайне тяжелым течением COVID‑19 (даже в том случае, если от момента появления симптомов прошло менее 7 дней) и склоняться в пользу отказа от применения кортикостероидов при лечении пациентов, не имеющих тяжелой формы заболевания (даже в том случае, если от момента появления симптомов прошло более 7 дней). Необходимо также принять во внимание наличие у пациента эндемичных инфекционных заболеваний, течение которых может усугубиться на фоне приема кортикостероидов. Например, при использовании стероидов в районах с эндемичным распространением стронгилоидоза, необходимо принять во внимание риск активизации возбудителя Strongyloides stercoralis на фоне приема кортикостероидов в целях лечения, диагностики или эмпирической терапии. Фактические сведения, лежащие в основе данной рекомендации Преимущества и вред Рекомендация вынесена экспертной группой на основании фактических данных с низкой степенью убедительности, свидетельствующих о возможном увеличении 28‑дневной смертности на 3,9% среди пациентов с COVID‑19, которые не находятся в крайне тяжелом состоянии. Степень убедительности фактических данных для данной подгруппы была снижена в связи с существенной неоднозначностью трактовки (т.е. фактические сведения не позволяют исключить сокращения смертности), а также вероятностью систематической ошибки из‑за отсутствия маскировки данных. При вынесении условной рекомендации против произвольного применения системных кортикостероидов экспертная группа исходила из предположения о том, что большинство полноценно информированных лиц с нетяжелым течением заболевания будут склонны отказаться от системной терапии кортикостероидами, и в то же время значительная часть пациентов может склоняться к обсуждению этого варианта терапии с лечащими врачами (161)(6). Примечание. В случае, если у беременной женщины имеется риск преждевременных родов на сроке беременности от 24 до 34 недель ВОЗ рекомендует назначение лечения кортикостероидами в дородовом периоде при условии отсутствия признаков материнской инфекции и доступности надлежащей акушерской и неонатальной помощи. Тем не менее, при наличии у пациентки COVID‑19 легкого или среднетяжелого течения, клинические преимущества, связанные с антенатальным применением кортикостероидов, могут превосходить вероятный риск вреда для матери. В этом случае в целях достижения информированного решения необходимо обсудить соотношение пользы и вреда для женщины и недоношенного младенца с самой пациенткой, так как оно может определяться клиническим состоянием женщины, ее собственными предпочтениями и пожеланиями членов семьи, а также доступностью ресурсов здравоохранения. Убедительность фактических данных См. раздел «Преимущества и вред». Ценностные ориентиры и предпочтения Слабая или условная рекомендация сделана в связи с возможными различиями ценностных ориентиров и предпочтений пациентов. По мнению экспертной группы, большинство лиц с нетяжелым течением заболевания будут склонны отказаться от применения системных кортикостероидов. Тем не менее многие пациенты могут предпочесть данное вмешательство после консультации с лечащим врачом. Ресурсная оснащенность и другие аспекты Необходимость в ресурсной оснащенности, практическая осуществимость, обеспечение равноправия и соблюдения прав человека Кроме того, экспертная группа пришла к выводу о том, что в интересах гарантированного доступа пациентов с тяжелым и крайне тяжелым течением COVID‑19 к системным кортикостероидам, следует избегать назначения этого вмешательства тем пациентам, которым, исходя из имеющихся в настоящее время фактических сведений, оно может не принести пользы. Обоснование Данная рекомендация была вынесена на основании консенсусного решения. Возможность применения Действие этой рекомендации распространяется на пациентов с нетяжелым течением заболевания, независимо от их нахождения на стационарном лечении. Экспертная группа отметила, что для пациентов с нетяжелым течением COVID‑19, как правило, не требуется экстренная госпитализация или респираторная поддержка; тем не менее в ряде стран данные пациенты могут подлежать госпитализации исключительно в целях изоляции, и в этом случае не следует назначать лечение кортикостероидами для системного применения. Группа пришла к выводу о том, что лечение кортикостероидами для системного применения не следует отменять в том случае, если оно было назначено пациентам ранее по другим причинам (например, пациенты с хронической обструктивной болезнью легких или другими заболеваниями аутоиммунной природы не должны прекращать курс лечения системными кортикостероидами для приема внутрь). В случае ухудшения клинической картины у пациента с нетяжелым течением COVID‑19 (то есть повышение частоты дыхательных движений, возникновение признаков дыхательной недостаточности или гипоксемии) необходимо назначение системной терапии кортикостероидами (см. рекомендацию в отношении пациентов с тяжелым и крайне тяжелым течением COVID-19). 119 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Клиническая проблема/вопрос PICO Популяция: пациенты с нетяжелым течением COVID-19 Вмешательство: системные кортикостероиды Сравнение: стандарт оказания помощи Резюме Резюме фактических данных В приведенном ранее резюме фактических данных (размещенном в разделе рекомендаций для пациентов с тяжелым и крайне тяжелым течением COVID-19) содержится дополнительная информация о восьми РКИ, рассмотренных в двух систематических обзорах с метаанализом. В нем также представлены сведения о дополнительных систематических обзорах, проведенных в целях оценки профиля безопасности, и результатах анализа в подгруппах, послуживших основой для вынесения отдельных рекомендаций в отношении пациентов с нетяжелой формой COVID-19 и пациентов с тяжелой и крайне тяжелой формами этого заболевания. В сводной таблице результатов наблюдений, составленной в соответствии с методологией GRADE, представлены относительные и абсолютные эффекты применения системных кортикостероидов для лечения пациентов с нетяжелым течением COVID-19 по сравнению со стандартом оказания помощи в разбивке по конечным результатам, представляющим интерес, с указанием соответствующей степени убедительности данных. Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство Системные кортикостероиды Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Смертность 28 дней относительный риск: 1,22 (95% ДИ: 0,93–1,61) Данные по 1535 пациентам, полученные в 1 исследовании1 Последующее наблюдение: 28 дней. 23 на 1000 28 на 1000 Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных2 Применение системных кортикостероидов может приводить к увеличению риска 28‑дневной смертности у пациентов с нетяжелым течением COVID‑19. Разница: увеличение на 5 случаев на 1000 (95% ДИ: сокращение на 2 случая – увеличение на 14 случаев) Потребность в инвазивной искусственной вентиляции легких 28 дней относительный риск: 0,74 (95% ДИ: 0,59–0,93) На основании данных по 5481 пациенту в 2 исследованиях. Последующее наблюдение: 28 дней. 116 на 1000 86 на 1000 Средняя Ввиду высокой вероятности систематической ошибки3 Применение системных кортикостероидов, по‑видимому, снижает потребность в искусственной вентиляции легких. Разница: сокращение на 30 случаев на 1000 (95% ДИ: сокращение на 48 случаев – сокращение на 8 случаев) Желудочно- кишечное кровотечение относительный риск: 1,06 (95% ДИ: 0,85–1,33) На основании данных по 5403 пациентам в 30 исследованиях4 48 на 1000 51 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных5 Прием кортикостероидов, вероятно, не приводит к увеличению риска желудочно- кишечных кровотечений. Разница: увеличение на 3 случая на 1000 (95% ДИ: сокращение на 7 случаев – увеличение на 16 случаев) Случаи суперинфекции относительный риск: 1,01 (95% ДИ: 0,9–1,13) На основании данных по 6027 пациентам в 32 исследованиях. 186 на 1000 188 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных6 Прием кортикостероидов, вероятно, не приводит к увеличению риска суперинфекции. Разница: увеличение на 2 случая на 1000 (95% ДИ: сокращение на 19 случаев – увеличение на 24 случая) Гипергликемия Относительный риск: 1,16 (95% ДИ: 1,08–1,25) На основании данных по 8938 пациентам в 24 исследованиях. 286 на 1000 332 на 1000 Средняя Ввиду крайне косвенного характера данных7 Прием кортикостероидов предположительно приводит к повышению риска гипергликемии. Разница: увеличение на 46 случаев на 1000 (95% ДИ: увеличение на 23 случая – увеличение на 72 случая) 120 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Конечный результат временные рамки Результаты исследования и количественные показатели Сравнение стандарт оказания помощи Вмешательство Системные кортикостероиды Убедительность фактических данных (качество фактических данных) Резюме в текстовом формате Гипернатриемия Относительный риск: 1,64 (95% ДИ: 1,32–2,03) На основании данных по 5015 пациентам в 6 исследованиях. 40 на 1000 66 на 1000 Средняя Ввиду крайне косвенного характера данных8 Прием кортикостероидов предположительно приводит к повышению риска гипернатриемии. Разница: увеличение на 26 случаев на 1000 (95% ДИ: увеличение на 13 случаев – увеличение на 41 случай) Нейромышечные расстройства, проявляющиеся слабостью Относительный риск: 1,09 (95% ДИ: 0,86–1,39) На основании данных по 6358 пациентам в 8 исследованиях. 69 на 1000 75 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных9 Прием кортикостероидов, вероятно, не приводит к увеличению риска нейромышечных расстройств, проявляющихся слабостью. Разница: увеличение на 6 случаев на 1000 (95% ДИ: сокращение на 10 случаев – увеличение на 27 случаев) Психоневротические состояния Относительный риск: 0,81 (95% ДИ: 0,41–1,63) На основании данных по 1813 пациентам в 7 исследованиях. 35 на 1000 28 на 1000 Низкая Ввиду крайне косвенного характера и существенной неоднозначности трактовки данных10 Прием кортикостероидов, вероятно, не приводит к увеличению риска развития психоневротических состояний. Разница: сокращение на 7 случаев на 1000 (95% ДИ: сокращение на 21 случай – увеличение на 22 случая) Продолжительность госпитализации Единица измерения: день Предпочтителен более низкий уровень На основании данных по: 6425 участникам в 1 исследовании (рандомизированные контролируемые) 13 дней 12 дней Низкая Ввиду высокой вероятности систематической ошибки и существенной неоднозначности трактовки данных11 Применение стероидных средств, вероятно, приводит к существенному сокращению продолжительности госпитализации. 1. Систематический обзор [1]. Уровень для сравнения/группа сравнения: первичное исследование [15]. Данные о смертности в исходный момент времени и искусственной вентиляции легких получены из контрольной группы исследования ВОЗ SOLIDATIRY. 2. Риск систематической ошибки: существенный. Отсутствие маскировки данных. Неоднозначность трактовки данных: существенная. 3. Риск систематической ошибки: существенный. Отсутствие маскировки данных. 4. Систематический обзор. Уровень для сравнения/группа сравнения: контрольная группа исследования, по данным которого изучается вмешательство. Справочные материалы: [1], 5. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 6. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 7. Косвенный характер данных: существенный. 8. Косвенный характер данных: существенный. 9. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 10. Косвенный характер данных: существенный. Неоднозначность трактовки данных: существенная. 11. Риск систематической ошибки: существенный. Отсутствие маскировки данных. Неоднозначность трактовки данных: существенная. Доверительный интервал не накрывает область, соответствующую полезному эффекту. 121 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 7. Методы: каким образом велась разработка этого рекомендательного документа Данный документ, содержащий текущие вариативные рекомендации ВОЗ, был составлен в соответствии со стандартами и методами подготовки качественных рекомендаций, а также с применением инновационных процессов эффективного обновления рекомендаций. Методы приведены в соответствие с Пособием ВОЗ по разработке руководящих принципов, а также с предварительно утвержденным протоколом (предложение о планировании) Комитета ВОЗ по разработке руководящих принципов (161). Другие руководящие указания по теме Данные вариативные рекомендации ВОЗ по лечению COVID-19 согласованы с более комплексным руководящим документом «Клиническое ведение случаев COVID-19: вариативные рекомендации», который охватывает более широкий круг тем и регулярно обновляется (6). Первые десять версий этих вариативных рекомендаций ВОЗ под названием «Лекарственная терапия при COVID-19», в которых рассматривается применение кортикостероидов, ремдесивира, гидроксихлорохина, комбинации лопинавира и ритонавира, ивермектина, блокаторов рецепторов к IL-6, комбинации казиривимаба и имдевимаба (нейтрализующие моноклональные антитела), плазмы реконвалесцентов, ингибиторов JAK, сотровимаба, молнупиравира, ремдесивира и комбинации нирматрелвира и ритонавира доступны на веб-сайте ВОЗ (4). Рекомендации, касающиеся лекарственных средств для профилактики (не лечения) COVID-19, представлены в отдельном документе: "WHO Living guideline: Drugs to prevent COVID-19" (Лекарственные средства для профилактики COVID‑19: вариативные рекомендации), который доступен на веб‑сайте ВОЗ и в журнале BMJ (8). Временные рамки Данные рекомендации носят вариативный характер; по мере поступления новых фактических сведений, которые требуют внесения изменений, ведется их постоянное обновление и распространение в глобальном масштабе (162). Поставлена задача по разработке и опубликованию рекомендаций ВОЗ в течение шести недель от момента обнародования результатов исследований, требующих выпуска обновленной версии, без ущерба для стандартов и методологии создания качественных рекомендаций ["WHO Handbook for Guideline Development" (Пособие ВОЗ по разработке руководящих принципов)] (161)(163). Поэтапный подход В этом разделе представлен подход на основе одновременно разворачивающихся процессов для повышения эффективности и своевременности разработки и распространения вариативных рекомендаций высокого качества. Этап 1. Мониторинг, учет и объединение фактических данных В рамках постоянного систематического обзора и сетевого метаанализа (СМА), проводимых силами опытных специалистов в области обработки информации, которые изучают все информационные источники, посвященные новым РКИ в сфере борьбы с COVID-19, непрерывно ведется комплексный ежедневный мониторинг всех новых РКИ. Учет предварительно опубликованных данных, которые еще не прошли экспертную оценку, способствует быстрому обмену данными при чрезвычайной ситуации в области общественного здравоохранения, а включение таких данных в анализ способствует ускорению оценки средств для лекарственной терапии COVID-19 и их внедрению в клиническую практику. Методические рекомендации подлежат периодическому пересмотру, поскольку необходимо учитывать как фактические данные, прошедшие экспертную оценку за истекший период, так и новые данные. При появлении фактических данных, которые могут оказать влияние на практическую работу или привлекают внимание мировой общественности, Руководящий комитет ВОЗ по терапевтическим средствам инициирует процесс разработки рекомендаций. Решение о разработке или обновлении какой‑либо рекомендации основано на следующих критериях (любой из них может инициировать разработку рекомендаций): • вероятность того, что данная рекомендация приведет к изменению практики работы; • достаточный объем сведений о лечебном мероприятии, полученных в РКИ, для обоснования качественных доказательных данных систематического обзора; • актуальность для глобальной аудитории. Этап 2. Созыв совещания группы по разработке руководящих принципов В целях обеспечения глобальной географической представленности, гендерного баланса, соответствующего технического и клинического опыта, а также участия представителей пациентов при формировании группы ВОЗ провела отбор кандидатов. Для каждого мероприятия Технический отдел провел сбор и рассмотрение деклараций интересов и установил, что конфликта интересов не имелось ни у кого из членов группы. В ходе заседания участники получили формы декларации интересов, кроме того, Секретариат ВОЗ разъяснил процедуру декларирования интересов, и членам группы была предоставлена возможность заявить о любых других интересах, не отраженных в форме. Заявлений об таких конфликтах сделано не было. В ходе проведения поиска в сети Интернет никаких других интересов, которые могли бы повлиять на объективность или независимость суждений того или иного эксперта в процессе подготовки рекомендаций, выявлено не было. Для рассмотрения тематик флувоксамина и колхицина 7 апреля 2022 г. было созвано совещание ранее сформированной экспертной группы по разработке руководящих принципов (см. раздел 10). На совещании были рассмотрены основы методологии GRADE, включая формулировку вопросов по PICO (популяция, вмешательство, сравнение, исход) и исследуемые подгруппы, а также приоритизация важных для пациентов результатов (см. описание этапа 4 далее). Впоследствии группой была проведена аналитическая работа, в том числе анализ в заранее определенных группах результаты которого изложены в сводной таблице результатов наблюдений, рассмотрение проблем с точки зрения пациентов и аспекты практической реализации вмешательств, после чего были подготовлены рекомендации. Кроме того, группа по разработке руководящих принципов провела анализ механизма действия и доклинических фактических данных, касающихся безопасности. 122 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Этап 3. Объединение фактических данных По запросу Руководящего комитета ВОЗ по терапевтическим средствам группа по проведению постоянного систематического обзора / СМА провела независимый систематический обзор в целях изучения преимуществ и отрицательных эффектов рассматриваемого вмешательства (1). В состав группы по систематическому обзору вошли специалисты в области систематического обзора, клиницисты, клинические эпидемиологи и биостатистики. Члены данной группы обладают опытом работы по методологии GRADE и оценке убедительности фактических данных, в частности полученных в результате проведения СМА, в том числе по методу прямого и непрямого сравнения лечебных альтернатив. Группа по проведению СМА была проинформирована о результатах первоначального совещания экспертной группы по разработке руководящих принципов и уделила особое внимание исходам и подгруппам, которым эксперты отдали приоритет, после чего были подготовлены резюме фактических данных по методологии GRADE для обоснования рекомендаций. В случаях, если в РКИ отсутствовали прямые сравнения искомых лекарственных средств, группа по проведению ОДСМА выполняла косвенные сравнения с последующей подготовкой дополнительных резюме по методологии GRADE, которые впоследствии использовались группой по разработке руководящих принципов для обоснования рекомендаций. Коллектив методологов выполнил оценку достоверности выделения подгрупп с применением инструмента ICEMAN (110). Для каждого мероприятия технический отдел провел сбор и рассмотрение деклараций интересов и установил, что конфликта интересов не имелось ни у кого из членов группы по проведению систематического обзора. Этап 4. Окончательные рекомендации На основе методологии GRADE была определена степень убедительности фактических данных, а также характер и сила рекомендаций (164)(165). Для продолжения работы группы по разработке руководящих принципов в случае невозможности достижения консенсуса были предусмотрены процедуры голосования a priori. При подготовке рекомендаций эти процедуры не потребовались. При формулировке транспарентных и качественных рекомендаций были учены следующие важные факторы: • данные об абсолютной пользе и отрицательных эффектах, связанных с каждым из важных для пациентов конечных результатов, полученные на основе структурированных сводок фактических данных (например, сводная таблица результатов наблюдений, подготовленная по методологии GRADE) (166); • качество/убедительность фактических данных (164)(167); • ценностные ориентиры и предпочтения пациентов (168); • ресурсная оснащенность и другие аспекты (включая соображения практической осуществимости, применимости, равноправия) (168); • расчетная величина эффекта и доверительные интервалы для каждого исхода с указанием соответствующей степени убедительности в соответствии с таблицами резюме наблюдений. При отсутствии таких данных группа по разработке руководящих принципов рассматривает резюме в описательном виде (166); • согласно методологии GRADE, рекомендации характеризуются по своей силе как условные либо настоятельные. В случае несогласия членов группы по разработке руководящих принципов с оценкой фактических сведений или силы рекомендаций, ВОЗ применяет процедуру голосования по установленной методике (165)(168). По мере возможности в ходе обсуждения этих ключевых факторов члены экспертной группы опирались на данные научных исследований. При отсутствии таких данных руководствовались мнением специалистов, подкрепленным результатами опроса членов группы по разработке руководящих принципов, проводимого в соответствии с процедурой, описанной ниже. Преимущества и вред Члены группы по разработке руководящих принципов определили приоритеты конечных результатов (с точки зрения пациентов) по шкале от 9 [крайне важно] до 1 [не важно]) в группе пациентов с нетяжелым течением COVID-19 и в группе пациентов с тяжелым и крайне тяжелым течением COVID-19 (таблицы 1 и 2 ниже). Вопросы для членов группы были подготовлены в формате PICO (см. профиль фактических данных в разделе рекомендаций). Определение приоритетов проводилось путем опроса, наиболее поздний из которых состоялся в мае 2021 г. с последующим обсуждением результатов группой по разработке руководящих принципов. Конечные результаты, упорядоченные по приоритетности, использовались для обновления ОДСМА (2). Отбор и оценка значимости конечных результатов Члены группы по разработке руководящих принципов определили приоритеты конечных результатов с точки зрения пациентов с нетяжелым течением COVID-19 (таблица 1) и пациентов с тяжелой и крайне тяжелой формой этого заболевания (таблица 2). 123 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Таблица 1. Оценка конечных результатов с точки зрения пациентов с нетяжелым течением заболевания членами группы по разработке руководящих принципов Конечный результат Среднее значение СО Интервал Госпитализация 8,5 0,7 7–9 Летальный исход 8,1 1,9 3–9 Качество жизни 7,5 1,3 5–9 Серьезные побочные явления (например, побочные явления, приводящие к отмене препарата) 7,4 1,8 3–9 Время до исчезновения симптомов 7,3 1,7 4–9 Продолжительность госпитализации 6,6 0,9 5–8 Продолжительность оксигенации 6,6 1,2 5–9 Потребность в инвазивной искусственной вентиляции легких 5,9 2,3 1–8 Новая инфекция, не вызванная вирусом SARS-CoV-2 5,6 2,1 3–9 Время до элиминации вируса 5,5 2,4 1–9 Продолжительность инвазивной искусственной вентиляции легких 5,4 2,1 1–8 СО: стандартное отклонение. Примечание 7–9: крайне важно; 4–6: важно; 1–3: маловажно. Таблица 2. Оценка конечных результатов с точки зрения пациентов с тяжелым и крайне тяжелым течением заболевания членами группы по разработке руководящих принципов Конечный результат Среднее значение СО Интервал Летальный исход 9,0 0 9 Потребность в инвазивной искусственной вентиляции легких 8,2 0,9 6–9 Продолжительность инвазивной искусственной вентиляции легких 7,6 0,9 6–9 Качество жизни 6,9 1,3 5–9 Продолжительность госпитализации 6,7 1,2 4–9 Серьезные побочные явления (например, побочные явления, приводящие к отмене препарата) 6,7 1,8 3–9 Время до исчезновения симптомов 6,5 1,6 4–9 Новая инфекция, не вызванная вирусом SARS-CoV-2 6,4 1,8 3–9 Продолжительность оксигенации 6,3 1,3 4–9 Время до элиминации вируса 4,7 2,3 1–9 СО: стандартное отклонение. Примечание: 7–9: крайне важно; 4–6: важно; 1–3: маловажно. Получение величин абсолютного эффекта различных средств терапии При оценке величины исходного риска у пациентов с нетяжелым течением COVID-19 группа по разработке руководящих принципов использовала медианное значение данного показателя в контрольной группе РКИ, данные которых включались в анализ в рамках ОДСМА (1)(2). Группа по разработке руководящих принципов определила, что пороговой величиной исходного риска госпитализации является значение 10% (100 госпитализаций на 1000 пациентов), которое отражает абсолютную пользу изучаемых лекарственных средств (например, сокращение случаев госпитализации на 60 на 1000 пациентов). 124 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) По мнению членов группы по разработке руководящих принципов, наиболее актуальным источником фактических данных для оценки исходного риска смертности и искусственной вентиляции легких у пациентов с тяжелой и крайне тяжелой формами COVID-19 служит контрольная группа исследования SOLIDARITY, проводившегося в большом ряде стран и географических районов. Системные кортикостероиды в настоящее время являются стандартом лечения пациентов с тяжелым и крайне тяжелым течением COVID-19 (см. настоятельную рекомендацию ВОЗ от сентября 2020 г.). Поэтому оценочные величины исходного риска смертности и потребности в искусственной вентиляции легких, представленные в резюме фактических данных в отношении ингибиторов JAK, реконвалесцентной плазмы и блокаторов рецепторов к IL-6, были скорректированы с учетом лечебного эффекта применения кортикостероидов. Для оценки показателя смертности был взят оценочный показатель исходного риска наступления летального исхода, равный 13% (130 случаев на 1000 пациентов). В отношении других исходов группа по разработке руководящих принципов использовала медианное значение соответствующего показателя в контрольной группе РКИ, данные которых включались в анализ. Соображения, положенные в основу определения показателей исходного риска, представлены по каждой рекомендации. Группа по разработке руководящих принципов признала, что величины исходных рисков, а значит и абсолютных эффектов, могут значительно различаться в зависимости от географической локализации и меняться с течением времени. В связи с этим возможно, что лицам, использующим данные рекомендации, предпочтительно проводить оценку абсолютного эффекта на основе местных показателей частоты развития неблагоприятных исходов. Ценностные ориентиры и предпочтения Группа по разработке руководящих принципов не располагала достаточным объемом сведений, содержащих основанное на фактических данных описание опыта либо ценностных ориентиров и предпочтений пациентов в отношении решения о лекарственной терапии COVID-19. В связи с этим группа исходила из собственных представлений о том, какие аспекты будут иметь значение для хорошо информированных пациентов после тщательного анализа пользы, вреда и трудностей, связанных с лечением. Представления о ценностных ориентирах и предпочтениях пациентов были прежде всего основаны на личном опыте входивших в состав группы пациентов, которые сами перенесли COVID-19. Группа по разработке руководящих принципов согласилась с тем, что для хорошо информированных пациентов являются характерными следующие ценностные ориентиры и предпочтения: • Большинство пациентов склонны воздержаться от применения препаратов, влияние которых на важные для пациента исходы, по имеющимся фактическим данным, не установлено. Это положение приобретает особую важность в случае, если согласно фактическим данным, имеется незначительный терапевтический эффект на фоне риска серьезного вреда. • С другой стороны, на фоне весомых преимуществ и большей определенности в отношении как пользы, так и риска, большее количество пациентов предпочтет выбрать лечебное мероприятие. В дополнение к рассмотрению вопросов с точки зрения отдельного пациента группа также учитывала такие важные с точки зрения популяции аспекты, как необходимость в ресурсной оснащенности, приемлемость, равноправный доступ и ценовые соображения. Результаты обсуждения вопросов, касающихся ценностных ориентиров и предпочтений, а также связанных с ними соображений в отношении практической осуществимости и потребностей в ресурсах, представлены по каждой рекомендации. Этап 5. Внешний и внутренний обзор Группа внешних рецензентов рассмотрела окончательный вариант данного рекомендательного документа в целях выявления фактических ошибок и изложения замечаний в отношении ясности формулировок, а также специфики и последствий реализации рекомендаций в конкретных условиях. Технический отдел собрал и рассмотрел декларации интересов внешних рецензентов и установил, что конфликта интересов не имелось ни у кого из членов группы. Вместе с тем в соответствии с процедурами, изложенными в Пособии ВОЗ по разработке руководящих принципов (стр. 70), в ряде случаев, касающихся конкретных лекарственных средств, рекомендуется обратиться к техническому представителю фармацевтической компании с просьбой прокомментировать положения о новом препарате с точки зрения отрасли, так как замечания таких лиц или организаций в отношении проекта рекомендаций могут быть полезны для прогнозирования и разрешения противоречий, выявления фактических ошибок и укрепления взаимодействия между всеми заинтересованными сторонами. Замечания по вопросам реализации рекомендаций в конкретных условиях, высказанные представителями фармацевтических компаний, рассматриваются с учетом их интересов. В данном случае наличие конфликта интересов носит транспарентный характер, так как аффилиация этих лиц указывается в разделе «Выражение признательности». На заключительном этапе рекомендательный документ был рассмотрен и одобрен Комитетом ВОЗ по обзору руководящих принципов. 125 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 8. Как получить доступ и пользоваться этим рекомендательным документом? В этом документе представлены текущие рекомендации ВОЗ. Данные рекомендации носят вариативный характер, то есть они обновляются и дополняются новыми положениями, касающимися других видов лечения COVID-19. Как получить доступ к этому руководящему документу • На веб-сайте ВОЗ в формате PDF (4). Данная версия содержит всю информацию, представленную на платформе MAGICapp, и предназначается для лиц, не имеющих надежного доступа к Интернету. Ее также можно загрузить непосредственно с платформы MAGICapp (см. пиктограмму в форме зубчатого колесика в правом верхнем углу). • В приложении MAGICapp в онлайновом многоуровневом формате. Приложение содержит самую полную версию данных рекомендаций (см. подробное описание далее). • В разделе "BMJ Rapid Recommendations"(5). В этом разделе, ориентированном на практических врачей, имеется интерактивная инфографика, представляющая краткий обзор всех включенных в рекомендации средств лечения. • В приложении WHO Academy. В данном мобильном приложении, доступном для медицинских работников и населения в магазинах приложений Apple Store и Google Play, имеется полноценный раздел «Ведение случаев заболевания», в который входят подразделы «Руководящие документы», «Обучение» и «Практический инструментарий», в том числе последние учебные модули по лекарственной терапии COVID-19. В нем также содержатся рекомендации по лечению и другие руководства и учебные материалы ВОЗ по COVID-19, доступные для использования в автономном режиме. • WHO COVID-19 Clinical Care Pathway («Клиническое ведение случаев») – это новый инструмент, который содержит краткое и удобное обобщение этих рекомендаций для работников здравоохранения. Для содействия практическому осуществлению инструмент отражает взаимосвязь этих рекомендаций с руководящими указаниями ВОЗ « Диагностическое тестирование для определения вируса SARS-CoV-2 » и «Выявление антигенов в диагностике инфекции, вызванной вирусом SARS-CoV-2». Как пользоваться этим рекомендательным документом Размещение, распространение и обновление данных рекомендаций происходит в приложении MAGICapp, а их формат и структура обеспечивают для пользователей удобство работы и поиска (163). Реализована функция постоянного обновления информации, относящейся к действующим положениям, которая позволяет знакомиться с новыми данными наряду с актуальными рекомендациями. Цель размещения в онлайновом формате данных и инструментов, например инфографики, заключается в упрощении поиска и внедрении рекомендаций в практическую работу клинициста. Онлайновый многоуровневый формат данных разработан для упрощения поиска рекомендаций пользователями и дальнейшего изучения доказательной базы и других сведений, относящихся к практическому применению рекомендаций, включая инструменты для совместного принятия решений (содействие коллегиальному принятию решений) (163). На рисунке 4 показано, как онлайновый многоуровневый формат данных позволяет пользователю сначала отыскать рекомендацию, а затем подробно изучить доказательную базу и другие сведения, относящиеся к ее практическому применению. Кроме того, ожидается, что пользователи ознакомлены с понятиями настоятельной и условной рекомендации (данная характеристика отображается непосредственно под текстом рекомендации), а также с понятием степени убедительности фактических данных (степень уверенности в том, что оценки эффекта, полученные в научных исследованиях, отражают истинные размеры эффекта от применения рассматриваемого вмешательства). Дополнительные сведения по каждой рекомендации представлены в разбивке по следующим вкладкам. • Данные по итогам исследования. В этом разделе содержится подробная информация о положенных в основу рекомендации фактических данных научных исследований, представленная в виде сводных таблиц результатов наблюдений, подготовленных по методологии GRADE, и резюме фактических данных в описательном виде (показано на рисунке 4). • Фактические сведения, лежащие в основе данной рекомендации. В этом разделе изложены абсолютные преимущества и отрицательные эффекты рассматриваемого вмешательства, а также другие факторы, связанные с его внедрением: ценностные ориентиры и предпочтения пациентов, практические аспекты проведения лечения и соображения, касающиеся ресурсной оснащенности, применимости, практической осуществимости, обеспечения равноправного доступа и соблюдения прав человека. Указанные факторы имеют особенно важное значение при необходимости адаптации рекомендаций к национальным или местным условиям. • Обоснование. В данном разделе объясняется, каким образом экспертная группа проводила рассмотрение и интеграцию фактических данных, с тем чтобы на их основе определить критерии принятия решений по каждой рекомендации, уделяя особое внимание спорным и сложным вопросам. • Практические сведения. В этом разделе представлены такие сведения, как, например, режим дозирования, продолжительность назначения и способ введения препаратов или вопросы применения тестов для выявления пациентов в клинической практике. • Помощь в принятии решений. Инструменты для совместного принятия решений в клинической практике. 126 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Рисунок 4. Пример быстрого доступа к данным по итогам исследования и дополнения Сводной таблицы результатов наблюдений в соответствии с методологией GRADE информацией в текстовом формате Дополнительные учебные модули и инструменты внедрения, предназначенные для работников здравоохранения • Инструмент ВОЗ для прогнозирования потребностей в основных материалах и оборудовании для борьбы с COVID-19 (COVID-ESFT) предназначен для содействия правительствам, партнерам и другим заинтересованным сторонам в прогнозировании потребностей в конкретном объеме средств индивидуальной защиты, диагностического оборудования, расходных медицинских материалов, биомедицинского оборудования для терапии пациентов и основных лекарственных средств для поддерживающего ухода и лечения COVID-19. • Методическое пособие ВОЗ «Клиническое ведение тяжелой острой респираторной инфекции: версия, адаптированная для борьбы с COVID-19» содержит алгоритмы и практические инструменты, предназначенные для клинического персонала больниц неотложной помощи, которые оказывают помощь взрослым и детям с острой респираторной инфекцией, включая тяжелую пневмонию, острый респираторный дистресс-синдром, сепсис и септический шок. В ней содержится информация в отношении скрининга, тестирования, мониторинга и лечения. • Открытая веб-платформа ВОЗ Openwho.org, серия курсов по клиническому ведению заболеваний, предлагает полный цикл курсов по COVID-19, который охватывает весь путь оказания помощи пациенту, начиная со скринингового обследования и клинической сортировки и заканчивая лечением, реабилитацией и оказанием паллиативной помощи. • Исследование ВОЗ по мониторингу безопасности молнупиравира для лечения инфекции COVID-19 легкой и средней степени тяжести в странах с низким и средним уровнем дохода с использованием когортного метода мониторинга событий. Кроме того, настоящие вариативные рекомендации ВОЗ используются для обоснования деятельности, осуществляемой в рамках программы ВОЗ по преквалификации лекарственных препаратов. 127 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 9. Малоизученные вопросы, новые фактические данные и последующие научные исследования Рекомендации по лекарственным средствам для лечения COVID-19 отражают сохраняющуюся неопределенность в отношении влияния лечения на все важные для пациентов исходы. Кроме того, необходимы более качественные фактические сведения в отношении прогноза, а также ценностных ориентиров и предпочтений пациентов с COVID-19. В этом документе группой по разработке руководящих принципов изложены основные аспекты, которые касаются применения флувоксамина и колхицина и вызывают неопределенность, и дополняют аналогичную информацию предыдущих версий вариативных рекомендаций в отношении ремдесивира, комбинации нирматрелвира и ритонавира, молнупиравира, ингибиторов JAK, сотровимаба, плазмы реконвалесцентов, комбинации казиривимаба и имдевимаба, ивермектина, кортикостероидов, ремдесивира, гидроксихлорохина, комбинации лопинавира и ритонавира, а также блокаторов рецепторов к IL-6. Эти малоизученные вопросы могут лечь в основу дальнейших исследований, то есть процесса поиска более актуальных и убедительных фактических данных для обоснования стратегических мер и практической работы. Кроме того, в документе представлены новые данные, которые продолжают поступать из многочисленных клинических исследований, посвященных борьбе против COVID-19. Малоизученные вопросы и перспективы дальнейших исследований Флувоксамин Рекомендация экспертной группы отражает мнение ее членов о том, что имеющиеся фактические данные недостаточны для применения флувоксамина в целях лечения COVID-19. Вместе с тем группа не подразумевает доказанной неэффективности флувоксамина. Решение о дальнейшем анализе эффектов флувоксамина при COVID-19, по-видимому, будет определяться мнением заинтересованных сторон касательно альтернативных издержек в связи с предпочтительным анализом эффектов флувоксамина по сравнению с другими кандидатными видами лечения. Обсуждения в экспертной группе позволили выявить представленный ниже перечень нерешенных вопросов. • Каковы эффекты флувоксамина у пациентов с нетяжелой формой COVID-19, которые вместе с тем затронуты риском ухудшения состояния и имеют выраженные симптомы тревожности? • Каковы побочные эффекты применения флувоксамина у пациентов с нетяжелым течением COVID-19, затронутых риском ухудшения состояния? • Какая доля пациентов с нетяжелым течением COVID-19, затронутых риском ухудшения состояния, не может быть охвачена данным лечением из-за риска лекарственных взаимодействий? Группа предположила, что в условиях доступности эффективных средств терапии исследователям будет необходимо сформировать позицию в отношении целесообразности дальнейших сравнений флувоксамина с плацебо либо отсутствием лечения. В случае, если выгодная цена и доступность флувоксамина станут основанием для проведения дальнейших исследований, представляется логичным применение дизайна не меньшей эффективности. Колхицин Группа по разработке руководящих принципов сочла маловероятной возможность выявления в ходе дальнейших исследований подгруппы пациентов, которые могут получить пользу от приема колхицина. Ремдесивир и комбинация нирматрелвира и ритонавира • Четкие алгоритмы клинического прогнозирования, позволяющие определять индивидуальный риск госпитализации у пациентов с нетяжелой формой COVID-19 в целях наиболее точного выявления пациентов, которым рассматриваемое вмешательство принесет наибольшую пользу. • Резистентность, а также эффективность в отношении новых вариантов, вызывающих интерес. • Эффективность в группе лиц с ослабленным иммунитетом, вакцинированных, беременных и других подгрупп пациентов. • Оптимальная продолжительность лечения. • Комбинированная терапия другими сочетаниями препаратов против COVID-19 и прямое сравнение с другими противовирусными средствами. Молнупиравир • Потребность в клинических данных для изучения проблем безопасности и применимости (в том числе у детей, кормящих или беременных, у мужчин); долгосрочное воздействие на мутагенез и риск развития рака). • Четкие алгоритмы клинического прогнозирования, позволяющие определять индивидуальный риск госпитализации у пациентов с нетяжелой формой COVID-19 в целях наиболее точного выявления пациентов, которым рассматриваемое вмешательство принесет наибольшую пользу. • Данные, которые актуальны для решения индивидуальных и популяционных проблем, таких как возникновение резистентности и эффективность в отношении новых вариантов вируса. • Сравнительная эффективность молнупиравира и других вариантов лечения (например, моноклональными антителами или другими противовирусными препаратами) в популяции пациентов с нетяжелым течением заболевания, включая комбинированную терапию. 128 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) • Относительные соотношения нуклеотидов внутри клетки для эндогенных: клеточных линий молнупиравира и в животных моделях – для оценки генетической токсичности. • Легкость возникновения мутаций под селективным воздействием NHC в условиях in vitro, а также молнупиравира на животных моделях и у пациентов с инфекцией SARS-CoV-2. • Могут ли мутации, возникающие под давлением естественного отбора в условиях in vitro, in vivo или у человека: • приводить к снижению противовирусной активности NHC; • возникать в спайк-белке и/или обеспечивают ли они повышение репликативного потенциала/передачи инфекции. Ингибиторы JAK • Дополнительные преимущества для пациентов при совместном назначении барицитиниба и блокаторов рецепторов к IL-6 по сравнению с монотерапией этими препаратами. • Относительная польза тофацитиниба и руксолитиниба по сравнению с барицитинибом. • Эффективность и безопасность применения у детей, беременных и кормящих женщин. Сотровимаб • Четкие алгоритмы клинического прогнозирования, позволяющие определять индивидуальный риск госпитализации у пациентов с нетяжелой формой COVID-19 с целью наиболее точного выявления пациентов, которым рассматриваемое вмешательство принесет наибольшую пользу. • Эффективность и безопасность серонегативных пациентов с COVID-19 при тяжелой и крайне тяжелой форме заболевания, пациентов, зараженных новыми вариантами вируса, а также детей и беременных женщин. Плазма реконвалесцентов • Влияние применения при тяжелых и крайне тяжелых формах болезни (фактические данные в отношении большинства важных для пациентов исходов имеют низкую и среднюю степень убедительности). • Показатель смертности в долгосрочной перспективе, а также функциональные исходы у лиц, перенесших COVID-19. • Эффективность и безопасность применения у детей, беременных и кормящих женщин. • Влияние применения плазмы реконвалесцентов с высоким титром антител на показатели смертности и другие важные для пациентов исходы. • Эффекты применения плазмы у серонегативных пациентов. Комбинация казиривимаба и имдевимаба • Четкие алгоритмы клинического прогнозирования, позволяющие определять индивидуальный риск госпитализации у пациентов с нетяжелой формой COVID-19 в целях наиболее точного выявления пациентов, которым рассматриваемое вмешательство принесет наибольшую пользу. • Режим дозирования и способ введения у пациентов с нетяжелым и тяжелым/крайне тяжелым течением COVID-19. • Эффективность и безопасность применения у детей и беременных женщин. Блокаторы рецепторов к IL-6 • Показатель смертности в долгосрочной перспективе, а также функциональные исходы у лиц, перенесших COVID-19. • Данные о безопасности с точки зрения внутрибольничной инфекции. • Данные о детях, беременных и лицах с ослабленным иммунитетом. • Пациенты с нетяжелым течением COVID-19. • Иммунитет, а также риск последующего заражения, что может повлиять на риск смерти в 28-дневный период; • Исходы в зависимости от дозировки блокатора рецепторов к IL-6 и оптимального времени для начала курса. Ивермектин Принимая во внимание крайне низкую степень убедительности оценок, касающихся большинства важных исходов, которые представляют интерес, группа по разработке руководящих принципов пришла к выводу о том, что для вынесения дальнейших рекомендаций в отношении клинического использования необходимы дополнительные высококачественные клинические исследования данного препарата. В том числе имеется в виду проведение РКИ как в группах стационарных и амбулаторных пациентов, так и пациентов с различной тяжестью заболевания, получающих лечение ивермектином по различным схемам. В центре внимания данных исследований должны находиться важные для пациентов исходы, такие как смертность, качество жизни, потребность в госпитализации, потребность в инвазивной искусственной вентиляции легких и время до клинического или симптоматического улучшения. Кроме того, будет важно дать более полную характеристику возможных вредных последствий применения ивермектина у пациентов с COVID-19. 129 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Гидроксихлорохин Группа по разработке руководящих принципов полагает, что, несмотря на остающиеся малоизученные вопросы, единообразные результаты клинических испытаний у пациентов с различной тяжестью и локализацией патологического процесса не дают оснований ожидать выявления при дальнейших исследованиях подгруппы пациентов, у которых применение гидроксихлорохина может положительно повлиять на важнейшие исходы (смертность, потребность в искусственной вентиляции легких). Комбинация лопинавира и ритонавира Группа по разработке руководящих принципов полагает, что, несмотря на остающиеся малоизученные вопросы, единообразные результаты клинических испытаний у пациентов с различной тяжестью и локализацией патологического процесса не дают оснований ожидать выявления при дальнейших исследованиях подгруппы пациентов, у которых применение комбинации лопинавира и ритонавира может положительно повлиять на важнейшие исходы (смертность, потребность в искусственной вентиляции легких). Кортикостероиды • Показатель смертности в долгосрочной перспективе, а также функциональные исходы у лиц, перенесших COVID-19. • Пациенты с нетяжелым течением COVID-19 (то есть наличие пневмонии без гипоксемии). • Исходы лечения при одномоментном назначении дополнительных препаратов против COVID-19, например новых иммуномодуляторов. Особую важность приобретает изучение лекарственного взаимодействия этих средств с кортикостероидами для системного применения. Необходимо проведение сравнительных исследований системной терапии кортикостероидами с терапией каждым из средств для лечения тяжелой и крайне тяжелой формы COVID‑19, которые проходят испытания в настоящее время (включая ремдесивир) либо сравнение комбинации этих средств и кортикостероидов для системного применения с монотерапией кортикостероидами для системного применения. • Иммунитет, а также риск последующего заражения, что может повлиять на риск смерти в 28-дневный период; • Исходы лечения в зависимости от лекарственной формы стероидного препарата, дозировки и оптимального времени для начала курса. Новые фактические данные Беспрецедентный объем запланированных и продолжающихся исследований, посвященных борьбе против COVID-19 – 5000 РКИ по состоянию на май 2022 г.– свидетельствует о перспективе появления более актуальных и убедительных фактических данных для обоснования стратегических мер и практической работы (13) (см. приложение). Обзор зарегистрированных, а также проходящих в настоящее время испытаний средств для лечения и профилактики COVID-19 представлен в разделе текущих систематических обзоров зарегистрированных клинических испытаний средств для лечения COVID-19 на веб‑сайте Обсерватории данных по инфекционным болезням, в постоянном систематическом обзоре зарегистрированных клинических испытаний средств против COVID-19 [13], а также на веб‑сайте ВОЗ и других информационных ресурсов, например инициативы COVID-NMA. Большинство этих исследований характеризуются небольшим масштабом и различным методологическим качеством, в то время как крупные исследования, проходящие на национальных или международных платформах (например, RECOVERY, SOLIDARITY и DISCOVERY), в большей степени позволяют получить надежную доказательную базу для обоснования возможных вариантов лечения (14)(15)(16)(17). Кроме того, в подобных исследованиях существует возможность адаптации дизайна, стратегии набора участников и выбора исследуемых воздействий на основе новых наблюдений, примеры которых были представлены выше в разделе, посвященном малоизученным вопросам. 130 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) 10. Авторство, вклад, выражение признательности Авторство, вклад, выражение признательности ВОЗ выражает признательность всем участникам за совместные усилия, направленные на ускорение, повышение эффективности, обеспечение надежности и транспарентности данной деятельности. Руководящий комитет ВОЗ по терапевтическим средствам (состав комитета обновлен с учетом экспертов, принимавших участие в работе над вопросами применения флувоксамина и колхицина) В состав комитета, который был утвержден Директором Департамента повышения уровня готовности стран и Главным научным сотрудником ВОЗ, входят представители различных департаментов, расположенных в штаб-квартире и региональных бюро ВОЗ. Секретариат ВОЗ проводит регулярные совещания для обсуждения срока очередного обновления рекомендаций на основе фактических данных, полученных от группы ВОЗ по оперативному обзору, а также из других источников, и выбирает членов группы по разработке руководящих принципов для составления текущих рекомендаций. Джанет В. Диас (руководитель клинической группы по реагированию на COVID-19, Программа по чрезвычайным ситуациям в области здравоохранения, Женева); Джон Аппиа (руководитель направления ведения случаев заболевания, Региональное бюро ВОЗ для стран Африки); Лиза Аски (Департамент обеспечения качества, норм и стандартов); Сильвия Бертаньолио (Департамент по инфекционным и неинфекционным заболеваниям/ клиническая группа по реагированию на COVID-19); Киори Кодама (Региональное бюро ВОЗ для стран Восточного Средиземноморья); Крутика Куппалли (клиническая группа по реагированию на COVID-19, Программа по чрезвычайным ситуациям в области здравоохранения, Женева); Марта Ладо Кастро Риал (клиническая группа по реагированию на COVID-19, Программа по чрезвычайным ситуациям в области здравоохранения, Женева); Лоренцо Моха (Департамент политики и стандартов в области медицинской продукции); Олуфеми Оладапо (Департамент по вопросам охраны сексуального и репродуктивного здоровья и научным исследованиям); Дина Пфайфер (Европейское региональное бюро ВОЗ/ Программа по чрезвычайным ситуациям в области здравоохранения); Прянка Релан (клиническая группа по реагированию на COVID-19, Программа по чрезвычайным ситуациям в области здравоохранения, Женева); Людовик Ревей (Департамент по вопросам сбора данных и информации для здравоохранения, система урегулирования инцидентов в связи с COVID-19, Панамериканская организация здравоохранения); Васихаран Сатиямурти (Департамент по исследованиям в области здравоохранения, отдел по научной работе); Энтони Соломон (Департамент по борьбе с забытыми тропическими болезнями); Пушпа Виджезинге (руководитель направления ведения случаев заболевания, Региональное бюро для стран Юго‑Восточной Азии). При поддержке следующих сотрудников по проекту: Жюли Вири и Анни Колин (клиническая группа по реагированию на COVID-19, Программа по чрезвычайным ситуациям в области здравоохранения, Женева). Решения о разработке рекомендаций и созыв заседаний группы по разработке руководящих принципов находится полностью в сфере компетенции Руководящего комитета ВОЗ по терапевтическим средствам. Выражаем особую признательность группе ВОЗ по фармаконадзору за поддержку и вклад в подготовку данного обновленного издания: Ноха Иесса и Шанти Пал. Экспертная группа, участвовавшая в обновлении рекомендаций по применению флувоксамина. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Диптеш Арьял (больница «Медисити», Непал); Эрлина Бурхан (отдел инфекционных болезней, кафедра заболеваний органов дыхания и респираторной медицины, медицинский факультет, Университет Индонезии); Маурицио Чеккони (Исследовательский госпиталь Humanitas, Милан, Италия); Нерина Харли (Королевская больница Мельбурна, больница Эпворта, Мельбурн, Австралия); Манай Хела (Служба скорой медицинской помощи Туниса, Тунис); Дэвид Хи (Центр имени Стэнли Хо по лечению новых инфекционных заболеваний, Китайский университет Гонконга, Китай); Беверли Хант (Королевский колледж Лондона, Великобритания); Фабиан Альберто Хаймес Барраган (Университет Антиокьи, Медельин, Колумбия); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Сима Канда (пациент, входящий в состав комиссии, Онтарио, Канада); Яе Жан Ким (Медицинская школа Университета Сунгкюнкван, Медицинский центр Самсунг, Сеул, Республика Корея); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур); Ракеш Лодха (отделение педиатрии, Всеиндийский институт медицинских наук, Нью-Дели, Индия); Марк Мендельсон (отделение инфекционных заболеваний и ВИЧ, Больница Гроот Шур, Университет Кейптауна); Джованни Баттиста Мильори (отделение пульмонологии, клинический институт IRCCS); Эммануэль Нсутебу (Медицинский город шейха Шахбута, Абу-Даби); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Нида Кадир (кафедра пульмонологии и медицины критических состояний, Школа медицины Дэвида Геффена, Университет Калифорнии, Лос-Анджелес, Соединенные Штаты Америки); Андре Рикардо Араужу да Силва (отделение перинатальной помощи, Федеральный университет Флуминенсе, Бразилия); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Университетская клиника «Шарите», Берлин, Германия); Рональд Сванстром (факультет биохимии и биофизики Университета Северной Каролины, США); Тим Уйеки (отдел гриппа, Центры США по контролю и профилактике заболеваний, США); Шридхар Венкатапурам (Королевский колледж Лондона, Соединенное Королевство). 131 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Экспертная группа, участвовавшая в обновлении рекомендаций по применению колхицина. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Диптеш Арьял (больница «Медисити», Непал); Эрлина Бурхан (отдел инфекционных болезней, кафедра заболеваний органов дыхания и респираторной медицины, медицинский факультет, Университет Индонезии); Маурицио Чеккони (Исследовательский госпиталь Humanitas, Милан, Италия); Нерина Харли (Королевская больница Мельбурна, больница Эпворта, Мельбурн, Австралия); Манай Хела (Служба скорой медицинской помощи Туниса, Тунис); Дэвид Хи (Центр имени Стэнли Хо по лечению новых инфекционных заболеваний, Китайский университет Гонконга, Китай); Беверли Хант (Королевский колледж Лондона, Великобритания); Фабиан Альберто Хаймес Барраган (Университет Антиокьи, Медельин, Колумбия); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Сима Канда (пациент, входящий в состав комиссии, Онтарио, Канада); Яе Жан Ким (Медицинская школа Университета Сунгкюнкван, Медицинский центр Самсунг, Сеул, Республика Корея); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур); Ракеш Лодха (отделение педиатрии, Всеиндийский институт медицинских наук, Нью-Дели, Индия); Марк Мендельсон (отделение инфекционных заболеваний и ВИЧ, Больница Гроот Шур, Университет Кейптауна); Джованни Баттиста Мильори (отделение пульмонологии, клинический институт IRCCS); Эммануэль Нсутебу (Медицинский город шейха Шахбута, Абу-Даби); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Нида Кадир (кафедра пульмонологии и медицины критических состояний, Школа медицины Дэвида Геффена, Университет Калифорнии, Лос-Анджелес, Соединенные Штаты Америки); Андре Рикардо Араужу да Силва (отделение перинатальной помощи, Федеральный университет Флуминенсе, Бразилия); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Университетская клиника «Шарите», Берлин, Германия); Рональд Сванстром (факультет биохимии и биофизики Университета Северной Каролины, США); Тим Уйеки (отдел гриппа, Центры США по контролю и профилактике заболеваний, США); Шридхар Венкатапурам (Королевский колледж Лондона, Соединенное Королевство). Экспертная группа, участвовавшая в обновлении рекомендаций по применению ремдесивира. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Эрлина Бурхан (отдел инфекционных болезней, кафедра заболеваний органов дыхания и респираторной медицины, медицинский факультет, Университет Индонезии); Каролин С. Калфи (Калифорнийский университет, Сан-Франциско); Маурицио Чеккони (Исследовательский госпиталь Humanitas, Милан, Италия); Дункан Чанда (Институт медицинских исследований и обучения, Замбия); Ву Куок Дат (кафедра инфекционных заболеваний, Ханойский медицинский университет, Ханой, Вьетнам); Хейке Гедулд (отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Манай Хела (Служба скорой медицинской помощи Туниса, Тунис); Фредерик Жакериоз Бауш (отделение первичной медико-санитарной помощи, Университетская больница Женевы, Швейцария); Фабиан Альберто Хаймес Барраган (Университет Антиокьи, Медельин, Колумбия); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур); Ракеш Лодха (отделение педиатрии, Всеиндийский институт медицинских наук, Нью-Дели, Индия); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Сания Сабзвари (Университет Ага Хана, Карачи, Пакистан); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Ману Шанкар- Хари (Королевский колледж Лондона, Великобритания); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Университетская клиника «Шарите», Берлин, Германия); Рональд Сванстром (факультет биохимии и биофизики Университета Северной Каролины, США); Тим Уйеки (Отдел гриппа, Центры США по контролю и профилактике заболеваний, США); Шридхар Венкатапурам (Королевский колледж Лондона, Великобритания). Группа по разработке руководящих принципов, участвовавшая в разработке рекомендаций по применению комбинации нирматрелвира и ритонавира. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Эрлина Бурхан (отдел инфекционных болезней, кафедра заболеваний органов дыхания и респираторной медицины, медицинский факультет, Университет Индонезии); Каролин С. Калфи (Калифорнийский университет, Сан-Франциско); Маурицио Чеккони (Исследовательский госпиталь Humanitas, Милан, Италия); Дункан Чанда (Институт медицинских исследований и обучения, Замбия); Ву Куок Дат (кафедра инфекционных заболеваний, Ханойский медицинский университет, Ханой, Вьетнам); Стивен Фридмен (Медицинская школа им. Камминга, Университет Калгари, Канада); Хейке Гедулд (отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Беверли Хант (Королевский колледж Лондона, Великобритания); Фабиан Альберто Хаймес Барраган (Университет Антиокьи, Медельин, Колумбия); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет); Артур Квизера (Колледж наук о здоровье Университета Макерере, отделение интенсивной терапии Национальной специализированной больницы Мулаго, Уганда); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур); Thiago Lisboa (Coraçao Hospital, Sao Paulo, Brazil); Ракеш Лодха (отделение педиатрии, Всеиндийский институт медицинских наук, Нью-Дели, Индия); Эммануэль Нсутебу (Медицинский город шейха Шахбута, Абу-Даби); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Сания Сабзвари (Университет Ага Хана, Карачи, Пакистан); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Ману Шанкар- Хари (Королевский колледж Лондона, Великобритания); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Рональд Сванстром (факультет биохимии и биофизики Университета Северной Каролины, США); Тим Уйеки (отдел гриппа, Центры США по контролю и профилактике заболеваний, США); Шридхар Венкатапурам (Королевский колледж Лондона, Великобритания). 132 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Группа по разработке руководящих принципов, участвовавшая в разработке рекомендаций по применению молнупиравира. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Маурицио Чеккони (Исследовательский госпиталь Humanitas, Милан, Италия); Дункан Чанда (Институт медицинских исследований и обучения, Замбия); Ву Куок Дат (кафедра инфекционных заболеваний, Ханойский медицинский университет, Ханой, Вьетнам); Энн Де Саттер (Гентский факультет медицины и здравоохранения, Бельгия); Хейке Гедулд (Отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Патрик Ги (член группы пациентов, Вирджиния, США); Маттиас Готте (Университет Альберты, Канада); Нерина Харли (Королевская больница Мельбурна, больница Эпворта, Мельбурн, Австралия); Манай Хела (Служба скорой медицинской помощи Туниса, Тунис); Беверли Хант (Королевский колледж Лондона, Великобритания); Фабиан Альберто Хаймес Барраган (Университет Антиокьи, Медельин, Колумбия); Фредерик Жакериоз Бауш (отделение первичной медико-санитарной помощи, Университетская больница Женевы, Швейцария); Фьеза Джехан (Университет Ага Хана, Пакистан); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Яе Жан Ким (Медицинская школа Университета Сунгкюнкван, Медицинский центр Самсунг, Сеул, Республика Корея); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет Святого Георгия, Великобритания); Артур Квизера (Колледж наук о здоровье Университета Макерере, отделение интенсивной терапии Национальной специализированной больницы Мулаго, Уганда); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур); Тьяго Лисбоа (больница Корасао, Сан-Паулу, Бразилия); Имельда Махака (Пангея Зимбабве СПИД Траст, Хараре, Зимбабве); Эммануэль Нсутебу (Медицинский город шейха Шахбута, Абу-Даби); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Ману Шанкар-Хари (Королевский колледж Лондона, Великобритания); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Берлинский университет Шарите, Германия); Рональд Сванстром (Факультет биохимии и биофизики Университета Северной Каролины, США); Тим Уйеки (Отдел гриппа, Центры США по контролю и профилактике заболеваний, США); Шридхар Венкатапурам (Королевский колледж Лондона, Великобритания); Ананда Виджевикрама (Министерство здравоохранения, Шри-Ланка). Группа по разработке руководящих принципов, участвовавшая в разработке рекомендаций по применению ингибиторов JAK. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Каролин Калфи (Калифорнийский университет, Сан-Франциско); Дункан Чанда (Институт медицинских исследований и подготовки кадров, Замбия); Ву Куок Дат (Кафедра инфекционных заболеваний, Ханойский медицинский университет, Ханой, Вьетнам); Энн Де Саттер (Гентский факультет медицины и здравоохранения, Бельгия); Беверли Хант (Королевский колледж Лондона, Великобритания); Хейке Гедулд (Отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Яе Жан Ким (Медицинская школа Университета Сунгкюнкван, Медицинский центр Самсунг, Сеул, Республика Корея); Санджив Кришна (Лондонский университет); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Сания Сабзвари (Университет Ага Хана, Карачи, Пакистан); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Нью-Дели, Индия); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Шарите - Университет медицины Берлина, Германия); Шридхар Венкатапурам (Королевский колледж Лондона, Великобритания); Ананда Виджевикрама (Министерство здравоохранения, Шри-Ланка); Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур). Группа по разработке руководящих принципов, участвовавшая в разработке рекомендаций по применению сотровимаба. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Фабьен Альберто Хаймс Барраган (Университет Антьокия в Медельине, Колумбия); Дункан Чанда (Институт медицинских исследований и обучения, Замбия); Ву Куок Дат (кафедра инфекционных заболеваний, Ханойский медицинский университет, Ханой, Вьетнам); Энн Де Саттер (Гентский факультет медицины и здравоохранения, Бельгия); Хейке Гедулд (Отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Нерина Харли (Королевская больница Мельбурна, больница Эпворта, Мельбурн, Австралия); Беверли Хант (Королевский колледж Лондона, Великобритания); Фьеза Джехан (Университет Ага Хана, Пакистан); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью-Дели, Индия); Яе Жан Ким (Медицинская школа Университета Сунгкюнкван, Медицинский центр Самсунг, Сеул, Республика Корея); Ниранджан Киссун (факультет педиатрии и неотложной медицины, Университет Британской Колумбии, Ванкувер, Канада); Санджив Кришна (Лондонский университет Святого Георгия, Великобритания); Тьяго Лисбоа (больница Корасао, Сан-Паулу, Бразилия); Имельда Махака (Пангея Зимбабве СПИД Траст, Хараре, Зимбабве); Эммануэль Нсутебу (Медицинский город шейха Шахбута, Абу-Даби); Наталья Пшеничная (Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, Москва, Российская Федерация); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Дели, Индия); Ману Шанкар-Хари (Королевский колледж Лондона, Великобритания); Иньчжун Шен (Шанхайский клинический центр общественного здравоохранения, Университет Фудань, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеманн (Берлинский университет Шарите, Германия); Рональд Сванстром (Факультет биохимии и биофизики Университета Северной Каролины, США); Шридхар Венкатапурам (Королевский колледж Лондона, Великобритания); Ананда Виджевикрама (Министерство здравоохранения, Шри-Ланка), Йи-Син Лео (Национальный центр инфекционных заболеваний, Сингапур). 133 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Группа по разработке руководящих принципов, участвовавшая в разработке рекомендаций по применению плазмы реконвалесцентов. Список членов экспертной группы, участвовавших в разработке предыдущей версии документа, доступен по данной ссылке. Вагди Амин (Министерство здравоохранения и народонаселения, Египет); Эрлина Бурхан (отдел инфекционных болезней, кафедра заболеваний органов дыхания и респираторной медицины, медицинский факультет, Университет Индонезии); Каролин С. Калфи (Калифорнийский университет, Сан Франциско); Маурицио Чеккони (Научно-исследовательский госпиталь "Humanitas", Милан, Италия); Ву Кок Дат (Отделение инфекционных болезней, Ханойский медицинский университет, Вьетнам); Хейке Гедулд (Отделение экстренной медицины, Университет Стелленбоша, Южная Африка); Патрик Ги (пациент, входящий в состав комиссии, Соединенные Штаты Америки); Нерина Харли (Королевская больница Мельбурна, больница Эпворта, Мельбурн, Австралия); Мадиха Хашими (Университет Зиауддина, Карачи, Пакистан); Сушил Кумар Кабра (Всеиндийский институт медицинских наук, Нью‑Дели, Индия); Сима Канда (пациент, входящий в состав комиссии, Онтарио, Канада); Летиция Кавано-Дурадо (Научно-исследовательский институт, больница Кюрасау, Сан-Паулу, Бразилия); Ниранджан Киссун (Отделение педиатрии и экстренной медицины, Университет Британской Колумбии, Ванкувер, Канада); Грета Мино (Больница Альсивар, Гуаякиль, Эквадор); Наталья Пшеничная (Центральный научно- исследовательский институт эпидемиологии Роспотребнадзора, Москва, Россия); Нида Кадир (Кафедра пульмонологии и медицины критических состояний, Школа медицины Дэвида Геффена, Университет Калифорнии, Лос-Анджелес, Соединенные Штаты Америки); Сания Сабзвари (Университет Ага Хана, Карачи, Пакистан); Рохит Сарин (Национальный институт туберкулеза и респираторных заболеваний, Нью-Дели, Индия); Иньчжун Шень (Шанхайский клинический центр общественного здравоохранения, Фуданьский университет, Шанхай, Китай); Шалини Шри Ранганатан (Университет Коломбо, Шри-Ланка); Мириам Штегеман (университетская клиника «Шарите», Берлин, Германия); Сридхар Венкатапурам (Королевский колледж, Лондон); Ананда Виевиккрама (Министерство здравоохранения Шри-Ланки). Руководители методического направления Гордон Гайатт (казиривимаб и имдевимаб, ингибиторы JAK, комбинация нирматрелвира и ритонавира), Брам Рохверг (блокаторы рецепторов к IL-6, ивермектин, ремдесивир, лопинавир-ритонавир, реконвалесцентная плазма, молнупиравир, обновление по ремдесивиру), Рид Сименюк (гидроксихлорохин), Франсуа Ламонтань (кортикостероиды, сотровимаб, колхицин, флувоксамин, флувоксамин, колхицин). Руководители клинического направления Майкл Джейкобс (казиривимаб и имдевимаб, блокаторы рецепторов к IL-6, ивермектин, ремдесивир, гидроксихлорохин и лопинавир-ритонавир, ингибиторы JAK, обновление по ремдесивиру), Йи Син Лео (кортикостероиды), Летиция Кавано- Дурадо (реконвалесцентная плазма, сотровимаб, молнупиравир), Мириам Штегеманн (флувоксамин, колхицин). Эксперты‑методологи Арнав Агарвал (Университет Торонто, Канада); Томас Агорицас (Университетская больница Женевы. Швейцария); Ромина Бригнарделло-Петерсен (Университет им. МакМастера, Канада); Гордон Гайатт (Университет им. МакМастера, Канада); Джордж Томлинсон (University Health Network, Торонто, Канада); Пер Олав Вандвик (MAGIC, Университет Осло, Норвегия); Линан Цзэн (2-я университетская больница Западного Китая, Сычуаньский университет, Чэнду, Китай; Университет им. МакМастера, Канада). Комитет по сотрудничеству в интересах разработки рекомендаций, осуществляющий координацию взаимодействия ВОЗ и организации MAGIC в интересах оперативной разработки и распространения рекомендаций ВОЗ через различные платформы для публикаций: Томас Агорицас (MAGIC, Университетская больница Женевы); Джанет Диас (Всемирная организация здравоохранения), Хелен Макдоналд (British Medical Journal); Гордон Гайатт (Университет им. МакМастера, Канада); Арахна Сиахванг (Всемирная организация здравоохранения); Пер Олаф Вандвик (MAGIC, Университет Осло); Жюли Вири (Всемирная организация здравоохранения). Временные консультанты Выражаем особую признательность профессору Эндрю Оуэну (кафедра молекулярной и клинической фармакологии, университет Ливерпуля) за вклад в фармакокинетический анализ следующих средств: ивермектин, блокаторы рецепторов к IL-6, комбинация казиривимаба и имдевимаба, плазма реконвалесцентов, моноклональные антитела, ингибиторы JAK, сотровимаб, молнупиравир, комбинация нирматрелвира и ритонавира, ремдесивир (обновленные данные), флувоксамин, колхицин. Выражаем особую благодарность профессору Крэгу Томпсону (Оксфордский университет) за его вклад в диагностические исследования, относящиеся к рекомендациям по применению комбинации казиривимаба и имдевимаба. Группа внешних рецензентов ВОЗ выражает особую признательность внешним рецензентам за ценные замечания в отношении применения плазмы реконвалесцентов, блокаторов рецепторов к IL-6 и ивермектина, сотровимаба, молнупиравира, комбинации нирматрелвира и ритонавира, ремдесивира, флувоксамина и колхицина. Аула Аббара (организация «Врачи без границ»); Ясин Араби (Университет медицинских наук короля Сауда ибн Абдул Азиза, Саудовская Аравия); Марсио да Фонсека (организация «Врачи без границ»); Ричард Коджан (Альянс в поддержку международных медицинских действий); Каролина Нанкларес (организация «Врачи без границ») и Сашвин Сингх (организация «Врачи без границ»). ВОЗ выражает особую признательность Поле Дейкин («Редженерон Фармасьютикалс, Инк.»), которую пригласили прокомментировать рекомендации в отношении казиривимаба и имдевимаба (шестая версия) с целью выявления фактических ошибок и изложения замечаний в отношении ясности формулировок, а также специфики и последствий реализации рекомендаций в конкретных условиях. Их замечания были рассмотрены с учетом интересов компании "Regeneron Pharmaceuticals Inc". 134 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Выражаем особую благодарность Лизе Барри (Фармакологический отдел, больница «Гора Синай», Торонто) за вклад клинических фармацевтов в подготовку практических информационных бюллетеней (сотровимаб, молнупиравир, комбинация нирматрелвира и ритонавира, обновленная информация по ремдесивиру). ВОЗ выражает особую признательность Кристин Цанг (Больница Оксфордского университета, NHS Foundation Trust, Соединенное Королевство) за ее вклад в подготовку информационных листков с практическими сведениями (обновленные данные по молнупиравиру, комбинации нирматрелвира и ритонавира, ремдесивиру). Наблюдатель Саде Огунсала (колхицин и флувоксамин). Инфографика Выражаем особую признательность журналу BMJ за подготовку инфографики для данного рекомендательного документа. Финансовая помощь ВОЗ выражает огромную благодарность Фонду Билла и Мелинды Гейтс, Управлению общественного здравоохранения Норвегии и правительству Германии. Особая благодарность адресуется организации «Magic Evidence Ecosystem Foundation», которая оказывает ВОЗ безвозмездную методологическую поддержку. Группы по проведению метаанализа ВОЗ выражает особую признательность Группе по проведению постоянного систематического обзора/ОДСМА из Университета им. МакМастера Арнав Агарвал (Университет Торонто, Канада); Томас Агорицас (организация "MAGIC", Университетская больница Женевы Швейцария); Джессика Бартошко (Университет им. МакМастера, Канада); Ромина Бригнарделло-Петерсен (Университет им. МакМастера, Канада); Дерек К. Чу (Университет им. МакМастера, Канада); Рейчел Кубан (Университет им. МакМастера, Канада); Андреа Дарзи (Университет им. МакМастера, Канада); Тахира Девджи (Университет им. МакМастера, Канада); Бо Фан (Чунцинский медицинский университет, Чунцин, Китай); Кармен Фанг (William Osler Health Network, Торонто, Канада); Сигне Агнес Флотторп (Институт общественного здравоохранения, Университет Осло, Норвегия); Фарид Форутан (Университет им. МакМастера, Канада); Лонг Ге (Школа общественного здравоохранения, Университет Ланьчжоу, Ганьсу, Китай); Гордон Гайатт (Университет им. МакМастера, Канада); Ми Хань (Колледж медицины, Университет Чосон, Кванджу, Республика Корея); Диана Хилс-Ансделл (Университет им. МакМастера, Канада); Кимия Хонарманд (медицинский факультет университета Уэестерн, Лондон, Канада); Лянъин Хоу (Школа общественного здравоохранения, Университет Ланьчжоу, Ганьсу, Китай); Сяожун Хоу. Куази Ибрагим (Университет им. МакМастера, Канада); Ариэль Ицкович (сотрудник больницы Hospital Alemán, Буэнос- Айрес, Аргентина); Елена Кум (Университет им. МакМастера, Канада); Франсуа Ламонтань, Цинь Лю (Школа общественного здравоохранения и управления, Чунцинский медицинский университет, Чунцин, Китай); Марк Лоэб (Университет им. МакМастера, Канада); Мора Маркуччи (Университет им. МакМастера, Канада); Шелли Л. Маклеод (Институт экстренной медицины имени Шварца и Рейзмана, Sinai Health, Торонто, Канада); Шархзад Мотаги, (Университет им. МакМастера, Канада); Шринивас Мерти; Рим Мустафа (Университет им. МакМастера, Канада); Джон Ди Нири (Университет им. МакМастера, Канада); Гектор Пардо-Хернандес (Иберо-американский Кокрановский центр, Биомедицинский научно- исследовательский институт Сант-Пау [IIB Sant Pau], Барселона, Испания); Анила Касим (Университет им. МакМастера, Канада); Габриэль Рада (Epistemonikos Foundation, Сантьяго, Чили); Ирбаз бин Риас (Отделение гематологии и онкологии, Клиника Мейо в Рочестере, Рочестер, Соединенные Штаты Америки); Брам Рохверг (Университет им. МакМастера, Канада), Бехнам Садегирад (Университет им. МакМастера, Канада); Нигар Секерсиоглу (Университет им. МакМастера, Канада); Лулу Шенг (Школа общественного здравоохранения и управления, Чунцинский медицинский университет, Чунцин, Китай); Рид Семенюк; Ашвини Сриканта (Университет им. МакМастера, Канада); Шарлотта Свитцер (Университет Макмастера, Канада); Бритта Тендал (Школа общественного здравоохранения и профилактической медицины, Университет Монаша, Мельбурн, Австралия); Лехана Табане (Университет им. МакМастера, Канада); Джордж Томлинсон; Тари Тернер (Школа общественного здравоохранения и профилактической медицины, Университет Монаша, Мельбурн, Австралия); Пер Олав Вандвик (организация "MAGIC", Университет Осло, Норвегия), Робин Вернуий (кафедра нефрологии и изучения гипертонии, Университетский медицинский центр Утрехта, Нидерланды); Андрес Витери-Гарсия (фонд "Epistemonikos Foundation", Сантьяго, Чили); Йин Ван (Университет им. МакМастера, Канада); Лян Яо (Университет им. МакМастера, Канада); Чжикан Йе (Университет им. МакМастера, Канада); Дина Зерааткар (Университет им. МакМастера, Канада)(1)(2)(3). Выражаем особую благодарность членам Рабочей группы ВОЗ по оперативной оценке фактических сведений в отношении лечения COVID‑19 (REACT) за подготовленную публикацию: "Association of administration of interleukin-6 antagonists with mortality and other outcomes among hospitalized patients with COVID-19: a prospective meta-analysis" (116). Ману Шанкар-Хари; Клэр Вейл; Питер Дж. Годольфин; Дэвид Фишер; Джулиан Хиггинс; Франческа Спига; Елена Савович; Джейн Тирни; Нор Ариса Миснан; Габриэль Барон; Джули Бенбеништи; Линдси Берри; Никлас Броман; Александр Биази Кавальканти; Роос Колман; Стефани Де Байзер; Ленни Дерде; Пер Доминго; Шарифа Фарида Сайед Омар; Ана Фернандес- Крус; Тийс Феут; Фелипе Гарсия; Росарио Гарсия-Викунья; Исидоро Гонсалес-Альваро; Энтони Гордон; Ричард Хейнс; Оливье Эрмин; Питер Хорби; Нора Хорик; Кулдип Кумар; Барт Ламбрехт; Мартин Ландрей; Лорна Леал; Дэвид Ледерер; Элизабет Лоренци; Ксавье Мариетт; Николя Мерчанте; Нор Ариса Миснан; Шалини Мохан; Майкл Нивенс; Ярмо Окси; ХосеПерес- Молина; Реувен Пизов; Рафаэль Порчер; Симоне Постма; Рина Раджасуриар; Атхималаипет Раманан; Панкти Рейд; Авраам Рутгерс; Арансасу Санчо-Лопес; Тодд Сето; Сумати Шивапаласингам; Арвиндер Сингх Соин; Натали Стаплин; Джон Стоун; Гарт Стробен; Йонас Санден-Каллберг; Джулиан Торре-Сиснерос; Ларри Цай; Хуберт ван Хогстратен; Том ван Меертен; Вивиан Кордейро Вейга; Питер Вестервил; Сринивас Мерти; Джанет Диас; Джон Маршалл; Джонатан Стерн. Выражаем благодарность компаниям "Hetero", "Dr Reddy's Laboratories", "MSD" ("Merck" в США и Канаде) и "Ridgeback Biotherapeutics" за предоставление данных на этапе до опубликования, которые были использованы для проведения метаанализа в ходе подготовки девятого издания вариативных рекомендаций ВОЗ. 135 из 142 Лекарственная терапия при COVID-19: вариативные рекомендации – Всемирная организация здравоохранения (ВОЗ) Библиография 1. Siemieniuk RAC, Bartoszko JJ, Zeraatkar D, Izcovich A, Pardo-Hernandez H, Rochwerg B, et al. : Drug treatments for covid- 19: living systematic review and network meta-analysis [обновление 4]. BMJ 2020;370: m2980; публикация на ресурсе Pubmed, журнальная статья. 2. Siemieniuk RAC, Bartoszko JJ, Díaz Martinez JP, Kum E, Qasim A, Zeraatkar D, et al. : Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ 2021;374 n2231; журнальная статья. 3. 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