Science and Technology
  • World Health Organization
  • 09/26/2021
  • 2017 lượt đọc

Therapeutics and Covid-19

Therapeutics and Covid-19

1. Summary: what is this living guideline? 


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


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


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


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


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


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


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


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


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


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


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


How this guideline was created: A Guideline Development Group (GDG) of content experts, clinicians, patients, ethicists, and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. No conflict of interest was identified for any panel member or other contributors to the guideline development process. This living guideline represents an innovation from the World Health Organization (WHO), driven by the urgent need for global collaboration to provide trustworthy and evolving COVID-19 guidance informing policy and practice worldwide. WHO has partnered with the non-profit MAGIC Evidence Ecosystem Foundation (MAGIC) for methodologic support and development, and dissemination of living guidance for COVID-19 drugs to prevent (1) and treat  COVID-19 (2). These guidelines are also published in the BMJ (3)(4), supported by a living systematic review with network meta-analysis (LNMA) that informs the recommendations (5)(6)(7)(8).        


The latest evidence: The GDG's recommendations for casirivimab and imdevimab were informed by results from the LNMA that pooled data from four RCTs with 4722 patients with non-severe disease (9)(10), and one RCT (RECOVERY) with 9785 patients with severe or critical disease that included a crucial subgroup analysis examining effect modification associated with serological status (seropositive versus seronegative) (11). 


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


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


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


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


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


Info Box 


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


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


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


Please visit the WHO website for the latest version of the guidance (2), also available in the BMJ as Rapid Recommendations (4), together with the living network meta-analysis (LNMA) (5)(7)(6), a major evidence source for the guidelines. 


Guidelines with recommendations on prophylaxis against COVID-19 have been published separately (3), and the WHO COVID-19 Clinical management: living guidance can also be found separately (12). 


2. Abbreviations   


3. Background 


As of 2 September 2021, over 218 million people worldwide have been diagnosed with COVID-19, according to the WHO dashboard (13). The pandemic has thus far claimed more than 4.3 million lives (13). Vaccination is having a substantial impact on case numbers and hospitalizations in a number of high-income countries, but limitations in global access to vaccines mean that many populations remain vulnerable (13)(14). Even in vaccinated individuals, uncertainties remain about duration of protection and efficacy of current vaccines 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 (15).   


This living guideline responds to emerging evidence from RCTs on existing and new drug treatments for COVID-19. More than 4200 trials investigating interventions for COVID-19 have been registered or are ongoing (see section on emerging evidence) (16). Among these are large national and international platform trials (such as RECOVERY, WHO SOLIDARITY, REMAP-CAP and ACTIV) that recruit large numbers of patients in many countries, with a pragmatic and adaptive design (17)(18)(19)(20). These platform trials are currently investigating and reporting on numerous interventions, including antiviral monoclonal antibodies and immunomodulators. This rapidly evolving evidence landscape requires trustworthy interpretation and expeditious clinical practice guidelines to inform clinicians and health care decision-makers. 


3.1 What triggered this version of the guideline? 


This sixth version of the WHO living guideline addresses the use of casirivimab and imdevimab in two groups of patients: those with non-severe COVID-19, and those with severe and critical illness. It follows the availability of pre-prints of four trials, that are part of the larger adaptive randomised master protocol addressing patients with non-severe illness, and of the RECOVERY trial addressing severe and critically ill patients (9)(10)(11). 


Casirivimab and imdevimab are two distinct neutralizing monoclonal antibodies to the SARS-CoV-2 virus, and thus have a plausible mechanism of action for beneficial impact on COVID-19 illness. 


3.2 Who made this guideline? 


For the casirivimab and imdevimab recommendations, WHO convened a Guideline Development Group with 40 individuals, of whom 36 were content experts (clinicians, methodologists, scientists) and four were patients who previously had COVID-19. The methods chair (methodological expertise) and a clinical chair (content expertise) guided the GDG discussions. 


WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise. The technical unit collected and managed declarations of interests (DOIs) and found no GDG member to have a conflict of interest. In addition to 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. Web searches also did not identify any conflicts. The MAGIC Evidence Ecosystem Foundation provided methodological experts with high-level expertise in standards and methods for systematic reviews and guideline development, including GRADE. These experts helped to support each of the recommendations. In addition, MAGIC offered innovations in processes (BMJ Rapid Recommendations) and platforms (MAGICapp) for developing living guidance in user-friendly formats. The methodological experts were not involved in the formulation of recommendations. MAGIC also worked with the BMJ to coordinate the simultaneous scientific publication of the living WHO guidelines (4). 


3.3 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. 


The guideline is written, disseminated and updated in MAGICapp, with a format and structure that ensures user-friendliness and ease of navigation (22). It accommodates dynamic updating of evidence and recommendations that can focus on what is new while keeping existing recommendations, as appropriate, within the guideline. Section 4 outlines key methodological aspects of the living guideline process. In addition, the methodologic support team, under the coordination of the Guideline Collaboration Committee (see Section 9), worked with the BMJ to develop the presentation, communication and coordinate the simultaneous scientific publication of the living WHO guidelines (4). 


The guideline is available via: 


•    WHO website in PDF format (2) 


•    MAGICapp in online, multilayered formats 


•    WHO Academy app 


•    BMJ Rapid Recommendations (4) 


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) (22). 


Additional educational modules and implementation tools for health workers can be found via: 


•    WHO COVID-19 essential supplies forecasting tool (COVID-ESFT) 


•    WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation 


•    WHO Openwho.org clinical management course series 


•    WHO Academy app   


This living guideline from WHO is also used to inform the activities of the WHO Prequalification of Medicinal Products.  


4. 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 (2). 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) (23).    


Related guidelines 


This living WHO guideline for COVID-19 treatments is related to the larger, more comprehensive guidance for COVID-19 Clinical management: living guidance, which has a wider scope of content and has been regularly updated (12). The first five versions of this WHO Therapeutics and COVID-19: living guideline, addressing corticosteroids, remdesivir, hydroxychloroquine, lopinavir/ritonavir, ivermectin and IL-6 receptor blockers can be accessed via the WHO website (2). 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 (3). 


Timing 


This guidance is living – dynamically updated and globally disseminated once new evidence warrants a change in recommendations (21). The aim is for a 6-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) (22)(23).   


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 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   


The pre-selected expert GDG (see Section 9) convened on two occasions to address casirivimab and imdevimab. The first meeting, held on 27 May 2021, reviewed the basics of GRADE methodology including formulating population, intervention, comparator, outcome (PICO) questions and subgroups of interests, and prioritization of patient-important outcomes. Subsequent to the meeting, the GDG participated, through email correspondence, in a survey that elicited their views of the decrease in hospitalization that would prompt patients with non-severe COVID-19 to seek treatment with casirivimab and imdevimab. At the second meeting, held on 29 July, 2021, the GDG reviewed analyses, including pre-specified subgroup analyses presented in summary of findings tables, and considered an individual patient perspective and feasibility issues specific to this intervention, and formulated recommendations for both non-severe and severe and critical patients. 


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 intervention (5). 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. The NMA team considered deliberations from the initial GDG meeting, specifically focusing on the outcomes and subgroups prioritized by the GDG. The methods team rated credibility of subgroups using the ICEMAN tool (24).           


Step 4: Final recommendations      


The GRADE approach provided the framework for establishing evidence certainty and generating both the direction and strength of recommendations (25)(26). While a priori voting rules informed procedures if the GDG failed to reach consensus, these procedures proved unnecessary for this recommendation.          


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) (27); 


•    quality/certainty of the evidence (25)(28); 


•    values and preferences of patients (29); 


•    resources and other considerations (including considerations of feasibility, applicability, equity) (29); 


•    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 (27); 


•    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 (26)(29).      


Step 5: External and internal review     


The WHO guideline was externally reviewed (see Section 9) and approved by the WHO GRC.   


5. The latest evidence 


This section outlines what information the GDG requested and used in making their recommendation for casirivimab and imdevimab. 


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 (30) and have demonstrated antiviral activity in rhesus macaques and Syrian golden hamsters (31). 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 (10). 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 (32). 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 (33). Data available also suggest that when delivered in combination, activity remains for currently circulating variants of concern (34). 


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. 


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). These prioritized outcomes were used to update the LNMA (7). 


Baseline risk estimates 


The evidence summaries that informed the guideline recommendations report the anticipated absolute effects of casirivimab and imdevimab compared with usual care across all patient-important outcomes. The absolute effects of treatment are informed by the prognosis (i.e. baseline risk estimates) combined with the relative estimates of effects (e.g. RR, OR) obtained from the LNMA. 


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.   


Patients with non-severe illness 


Selecting and rating the importance of outcomes 


GDG members prioritized outcomes from the perspective of patients with non-severe illness (Table 1). 


Table 1. GDG outcome rating from the perspective of patients with non-severe illness.     


SD: standard deviation. 


Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. 


Evidence summary 


The LNMA evidence summary (7) was informed by four trials that enrolled 4722 patients with non-severe illness (9)(10). All trials were registered and presented in preprints. Table 3 shows trial characteristics.  Casirivimab and imdevimab probably reduces admission to hospital (moderate certainty evidence), the outcome was rated by the GDG of the highest importance for patients with non-severe COVID-19. The relative reduction in hospitalization (OR 0.29; 95% CI:  0.17–0.48) results in 39 fewer hospitalizations per 1000 patients (95% CI: 35 fewer to 21 fewer) when using using the baseline risk of hospitalization in the three trials (4.2%). The evidence certainty was rated down to moderate because of concerns about decreased efficacy against emerging SARS-CoV-2 variants. The absolute benefit in hospital reduction will be greatest in those at highest risk for hospitalization and lower for the majority of the population at low risk.


Casirivimab and imdevimab probably also reduces duration of hospitalization with a best estimate of a reduction from 9.6 to 8.2 days (mean difference [MD] 1.4 fewer days; 95% CI: 4.6 fewer to 1.8 more; moderate certainty evidence). The intervention results in very few allergic reactions and severe adverse events. 


Concerning mortality, pooled data from 4722 patients in the four RCTs showed trivial or no effects of casirivimab and imdevimab (moderate certainty evidence). The GDG rated down the certainty of evidence for indirectness: the absolute risk of mortality in the overall trial population was very low (2 in 1000) and it is still possible that there is a small but important mortality reduction in patients at greatest risk of hospitalization. The conclusion is similar for mechanical ventilation based on 3432 patients with a very low baseline risk for ventilation of 4 in 1000.


Subgroup analysis  We found no evidence of subgroup effects on age or time from onset of illness in patients with non-severe COVID-19. 


Baseline risk estimates (prognosis of patients with COVID-19) informing absolute estimates of effect 


For the non-severe COVID-19 patients, we used the median of the control arm of the four RCTs that contributed to the evidence. For hospital admission, the key outcome driving the recommendation in favour of casirivimab and imdevimab, this gave a baseline risk of 4.2% (42 in 1000). These trials recruited patients at elevated risk of being hospitalized, to increase statistical power in detecting potential treatment effects. This means that the baseline risk of 4.2% is appreciably higher than the risk for many patients with nonsevere COVID-19. Furthermore, the risks vary widely across patients, and the absolute benefit of administration of the intervention will be highly dependent on individual risk. 


Values and preferences 


For the non-severe illness, the limited availability of casirivimab and imdevimab in relation to the number of infected individuals proved a major concern. For non-severe illness, GDG members completed a survey in which they provided their view regarding the magnitude of reduction in hospitalization that would prompt patients to use casirivimab and imdevimab. The panel responses suggested that the majority of patients with a risk of hospitalization above 10%, and thus an absolute risk reduction of approximately 6%, would choose to receive treatment while a majority of those below that risk level would decline treatment. Large majorities of patients with risks substantially higher than 10% would choose to receive treatment and large majorities of those with substantially lower risks would decline. 


Patients with severe or critical illness 


Selecting and rating the importance of outcomes 


GDG members prioritized outcomes from the perspective of patients with severe or critical illness (Table 2). 


Table 2. GDG outcome rating from the perspective of patients with severe and critical illness.   


SD: standard deviation. 


Note: 7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance. 


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 (11). The trial was registered and presented in preprints. Table 3 shows trial characteristics. 


In the overall population of patients with severe and critical COVID-19, not taking serological status into account, it remains uncertain whether casirivimab and imdevimab result in an important effect on mortality (OR 0.94; 95% CI: 0.86–1.03; absolute effect estimate 8 fewer per 1000 patients; 95% CI: 18 fewer to 4 more; low certainty evidence). The evidence was rated as low certainty because of imprecision and indirectness; a high likelihood that casirivimab and imdevimab have, in the seronegative and seropositive patients included in the overall group, very different effects (see below). The evidence on need for mechanical ventilation and duration of hospitalization was rated as very low certainty, adding risk of bias due to lack of blinding as another concern. 


Subgroup analysis 


A highly credible subgroup effect demonstrated that casirivimab and imdevimab likely reduces mortality in patients who are seronegative but not in those who are seropositive. Based on data from 3153 patients in the RECOVERY trial, the anticipated relative risk reduction of death in seronegative patients receiving casirivimab and imdevimab was 0.85 (95% CI: 0.76–0.95; absolute effect estimate 39 fewer per 1000; 95% CI: 62 fewer to 13 fewer; moderate quality evidence due to concerns with imprecision and indirectness due to possible new SARS-CoV-2 variants in the future where benefit may change). In the seronegative patients, the intervention may reduce the need for mechanical ventilation (RR 0.87; 95% CI: 0.77–0.98; absolute effect estimate 42 fewer per 1000; 95% CI: 74 fewer to 6 fewer; low certainty due to serious risk of bias, indirectness, and imprecision). 


The credibility of the subgroup effect was evaluated using the ICEMAN tool (24). 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. Figure 1 presents the forest plot depicting the point estimate and confidence interval around the effects on mortality in the seropositive and seronegative, demonstrating benefit in the seronegative, a point estimate suggesting harm in the seropositive, and no overlap in the confidence intervals, a result corresponding to the p=0.001 in the test of interaction (11). 


Figure 1. 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). 


Baseline risk estimates (prognosis of patients with COVID-19) 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 the seronegative patients, we identified the control arm of the RECOVERY trial as the best source. For the seronegative, risk of death in both severe (26%; 260 per 1000) and critical (46%; 460 per 1000) was 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.         


Values and preferences   


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, both limited availability of therapeutics and the requirement for serological testing as part of clinical decision-making to identify the seronegative patients proved important. 


6. Who do the recommendations apply to?   



7. Recommendations for therapeutics 


7.1 Casirivimab and imdevimab (neutralizing monoclonal antibodies) 


For patients with non-severe COVID-19 (who do not meet criteria for severe or critical infection) 


Conditional recommendation   


We suggest treatment with casirivimab and imdevimab, conditional to those at highest risk of hospitalization.   


•    Whereas casirivimab and imdevimab achieves a substantial reduction in the relative risk of hospitalization, the absolute benefit will be trivial or unimportant in absolute terms for all but those at highest risk for which the intervention should be reserved. 


•    The panel identified a risk beyond 10% of being hospitalized for COVID-19 to represent a threshold at which most people would want to be treated with casirivimab and imdevimab. 


•    In the absence of credible tools to predict risk for hospitalization in people infected with COVID-19, typical characteristics of people at highest risk include lack of vaccination, older people, or those with immunodeficiencies and/or chronic diseases (e.g. diabetes). 


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 (600mg of each antibody). In the face of limited access and resource considerations, health systems will face choices concerning dose of casirivimab and 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 and 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 


Benefits and harms 


In non-severe patients, casirivimab and imdevimab probably reduces the risk of hospitalization and duration of symptoms. Casirivimab and imdevimab is unlikely to have serious adverse effects, including allergic reactions. 


Certainty of the Evidence 


The unavailability of an empirically developed and validated risk prediction tool for establishing patients’ risk of hospitalization represents 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 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. 


Preference and values 


Applying the agreed values and preferences (see Section 5), the GDG inferred that almost all well-informed patients at typical low risk of hospitalization would decline casirivimab and imdevimab and only those at higher risk (e.g. unvaccinated, older, or immunosuppressed) would choose the treatment. 


Resources and other considerations


Acceptability and feasibility 


The GDG noted that casirivimab and 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 and imdevimab be reserved for those at highest risk of hospitalization.  Major feasibility challenges include limited production of casirivimab and 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) (35). 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 randomised master protocol)(10) – and subcutaneous administration, which has been used in the prophylactic trial (32). 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). 


Justification 


A combination of the evidence, values and preferences, and feasibility contributed to the conditional recommendation for the use of casirivimab and 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 and 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.   


Clinical Question/ PICO      


Population:      Patients with non-severe COVID-19      


Intervention:      Casirivimab and imdevimab      


Comparator:      No casirivimab and imdevimab       


1.    Inconsistency: no serious. Indirectness: no serious. There is substantial variability in baseline risk of death between patients. REGN-COV2 may confer an important benefit in patients at higher risk of death.. Imprecision: no serious.  Publication bias: no serious. 


2.    Inconsistency: no serious. Indirectness: serious. There is substantial variability in baseline risk of mechanical ventilation between patients. REGN-COV2 may confer an important benefit in patients at higher risk of mechanical ventilation..  Imprecision: no serious. Publication bias: no serious. 


3.    Inconsistency: no serious. 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.. Imprecision: no serious. Publication bias: no serious. 


4.    Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. Publication bias: no serious. 


5.    Inconsistency: no serious. 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.. Imprecision: no serious. Publication bias: no serious. 


6.    Inconsistency: no serious. Indirectness: no serious. Imprecision: very serious. Publication bias: no serious.   


Clinical Question/ PICO      


Population:      Patients with severe or critical COVID-19, seronegative      


Intervention:      Casirivimab and imdevimab      


Comparator:      No casirivimab and imdevimab     


1.    Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. Single study. Publication bias: no serious. 


2.    Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. Single study. Publication bias: no serious.


3.    Risk of Bias: serious. Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. Publication bias: no serious. 


4.    Risk of Bias: serious. Inconsistency: no serious. Indirectness: serious. Imprecision: very serious. Publication bias: no serious. 


For patients with severe or critical COVID-19 


Conditional recommendation  


We suggest treatment with casirivimab and imdevimab, under the condition that the patient has seronegative status.   


•    With benefits of casirivimab and 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 and imdevimab is in addition to the current standard of care, which includes corticosteroids and IL-6 receptor blockers. 


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 randomised 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 and imdevimab. 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 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 and 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 infusion, patients should undergo monitoring for allergic reactions. 


Evidence To Decision 


Benefits and harms 


In the overall population of patients with severe and critical COVID-19, casirivimab and 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 and imdevimab probably reduce 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. 


Certainty of the Evidence 


In patients with severe and critical COVID-19, evidence for mortality was of low certainty because of imprecision and high likelihood that casirivimab and imdevimab have, in the seronegative and seropositive patients included in the overall group, very different effects. In this population, the evidence regarding the impact of the intervention on need for mechanical ventilation and duration of hospitalization was very low certainty 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 unimportant) and indirectness (variants may emerge in which casirivimab and 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. 


Preference and values 


Applying the agreed values and preferences (see Section 5), 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 and imdevimab. Other patients – those whose are seropositive or whose status is uncertain – are likely to decline the intervention. 


Resources 


Cost and availability 


Given the cost and availability of casirivimab and 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 and imdevimab are 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 SARSCoV-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 (36)(37)(38). 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 and 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 and 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) (10). 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 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 - Section 5). 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 on 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, on 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 and 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 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 and 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 and imdevimab therapy in those with established multi-organ failure (in whom the benefit is likely to be smaller). 


Justification 


In patients with severe or critical illness, the conditional recommendation in favour of casirivimab and imdevimab use reflects the likelihood that any benefits are restricted to patients who are seronegative. 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 and 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 casirivi



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