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7. Recommendations for therapeutics

7.1 IL-6 receptor blockers

We recommend not to use ivermectin in patients with COVID-19 except in the context of a clinical trial.

 

7.3 Hydroxychloroquine (published 17 December 2020)

We recommend against administering hydroxychloroquine or chloroquine for treatment of COVID-19.

7.4 Lopinavir/ritonavir (published 17 December 2020)

We recommend against administering lopinavir/ritonavir for treatment of COVID-19.

7.5 Remdesivir (published 20 November 2020)

We suggest against administering remdesivir in addition to usual care.

7.6 Systemic corticosteroids (published 2 September 2020)

We recommend systemic corticosteroids rather than no corticosteroids.

For patients with non-severe COVID-19 infection (absence of criteria for severe or critical infection)


8. 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 values and preferences of patients with COVID-19 infection. Here we outline key uncertainties for IL-6 receptor blockers identified by the GDG, adding to those for ivermectin, corticosteroids, remdesivir and hydroxychloroquine and lopinavir/ritonavir in previous versions of the living guideline. These uncertainties may inform future research, i.e. the production of more relevant and reliable 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

IL-6 receptor blockers (despite the strong recommendation, there are a number of uncertainties that persist):

  • 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 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 benefit from hydroxychloroquine on the most important outcomes (mortality, mechanical ventilation) given the consistent results in trials across disease severity and location.
 
Remdesivir and effects on:

  • critical outcomes of interest, particularly those that impact resource allocation, such as the need for mechanical ventilation, duration of mechanical ventilation and duration of hospitalization;
  • specific subgroups, such as different severities of illness, different time (days) since onset of illness, children and older adults, pregnant women, and duration of therapy;
  • long-term outcomes such as mortality at extended endpoints or long-term quality of life;
  • long-term safety and rare but important side-effects;
  • patient-reported outcomes such as symptom burden;
  • outcomes, when used in combination with other agents, such as, but not limited to, corticosteroids;
  • impact on viral shedding, viral clearance, patient infectivity.

    
Corticosteroids and effects on:    

  • long-term mortality and functional outcomes in COVID-19 survivors;
  • 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 3300 RCTs as of 1 July 2021 – implies that more reliable and relevant evidence will emerge to inform policy and practice [14]. 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 [14], 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 [15][16][17][18]. Such trials can also adapt their design, recruitment strategies and selection of interventions based on new insights, exemplified by the uncertainties outlined above.