Current and emerging treatments for COVID-19 patients

The pandemic spread of COVID-19 infection has greatly affected the activities of the global healthcare system. Many experts were forced to suspend some ongoing research in favor of developing and testing new drugs for the treatment of coronavirus patients. The main task of scientists was to select existing and create new effective drugs simultaneously with the creation of a clear evidence base for their positive action.

We have the opportunity to consider the most relevant drugs for today used for COVID-19 .

Remdesivir

A broad-spectrum antiviral agent that inhibits RNA-dependent RNA polymerase is included in the COVID-19 treatment protocol in the United States, the United Kingdom and several European countries. 

European and British experts allowed the drug to be used by children from 12 years of age, whose weight is more than 40 kg, as well as adults with pneumonia and the need for oxygen therapy. In the United States, the prescribing requirements for Remdesivir are the same, including emergency care for pediatric patients. [1],  [2], [3]

However, the WHO does not approve of the use of Remdesivir in inpatients as an additional component of the standard therapeutic regimen, regardless of the severity of the pathology. This is due to the absence of the effect of the drug on reducing mortality from COVID-19, or on the early disappearance of the symptoms of the disease, compared with standard therapy. [4]

The views of the representatives of the United States National Institutes of Health are as follows:

• Remdesivir is indicated for independent use (for patients with minimal need for oxygen therapy), or in combination with Dexamethasone (for patients requiring additional oxygenation).
• The appointment of Remdesivir in combination with Dexamethasone is recommended for patients who need high-flow oxygen therapy or non-invasive mechanical ventilation. If there are indications for invasive mechanical ventilation or extracorporeal membrane oxygen therapy, the drug should not be prescribed.
• It is possible to prescribe Remdesivir to patients who do not require oxygen therapy, but who have a tendency to progression of the pathology.
• It is recommended to use Remdesevir within 5 days (or until discharge from the hospital, if it happens earlier). It is allowed to extend the treatment course up to 10 days (in the absence of pronounced clinical improvement).
• The medication should not be used everywhere for inpatient treatment of patients who do not require oxygenation, with oxygen saturation values of more than 94%.

Due to the conflicting recommendations, before using this drug, you should familiarize yourself with the adapted COVID-19 treatment guidelines in your particular region. [5]

Imdevimab / Kasirivimab (REGN-COV2)

An intravenous drug, a mixture of antibodies of human immunoglobulin G-1, active against the causative agent of COVID-19, is under investigation. However, in American clinics, the medication is approved as an emergency aid for mild to moderately severe coronavirus infection in adults and children. The UK and European countries have not yet approved REGN-COV2, but the EPA continues to study the material within clinical trials. 

Intermediate studies have shown that Imdevimab / Kasirivimab reduces viral load from the initial moment to the seventh day, mainly in patients with a not yet triggered immune response, or with an initial high viral load. [6]

The ineffectiveness of the drug has been proven when used in inpatients, or in patients requiring oxygenation. The possibility of prescribing a medication in cases where there is no need for oxygenation, or in patients with the necessary low-flow oxygen therapy, is being investigated. [7]

The successful neutralization of the circulating B.1.1.7 and B.1.351 types of SARS-CoV-2 with the preparation was revealed.

Published data on the positive use of neutralizing monoclonal antibodies in order to prevent the disease in persons who are in contact with COVID-19 patients at home: according to the results of the study, passive vaccination with REGN-COV2 made it possible to prevent symptomatic pathology in 100% of cases, and to halve the overall rates of symptomatic and asymptomatic infection. [8]

Before prescribing the drug, be sure to familiarize yourself with the features of the local treatment protocol.

Bamlanivimab

Another representative of intravenous neutralizing monoclonal antibodies - Bamlanivimab (LY-CoV555) - is under investigation. American experts have already approved the emergency use of the drug in therapeutic regimens for mild to moderate COVID-19 in childhood and adulthood. Other countries have not yet received approval. [9]

According to the recommendations of American experts, the use of Bamlanivimab can be indicated in patients with an increased risk of worsening the pathology. Among the contraindications are the severe course of COVID-19, the late stage of the disease, as well as daily outpatient practice.

According to the latest data, Bamlanivimab in combination with Etesevimab reduces the viral load on the 11th day (monotherapy did not show such an effect). No neutralization of circulating B.1.1.7 and B.1.351 types of pathology was found. [10]

According to the results of the BLAZE-2 study, the drug reduces the likelihood of infection in everyday life (nursing home) by 80%. [11]

The drug is undergoing the next stage of research, therefore, it cannot be recommended for a widespread prescription: it is necessary to focus on local treatment protocols.

Reconvalescent plasma

The blood serum of persons who have recovered from COVID-19 is a biomaterial containing ready-made antibodies. This drug is allowed to be used as an emergency aid for patients in inpatient departments of American clinics. Other countries continue to study the drug, considering insufficient information about it. [12],  [13], [14]

According to the latest data, the plasma of convalescents reduces the mortality of inpatient patients by 9% (if it was prescribed within three days after the diagnosis was made) or by 12% (if it was prescribed for 4 days or more). There is information about an increase in viral clearance and an increase in clinical improvement as a result of the use of plasma from patients who have been ill. The positive effect of early administration of the drug on reducing the progression of pathology and inhibition of its transformation into a severe form has been proven. [15], [16]

At the moment, additional studies are underway to assess the safety and efficacy of convalescent serum. [17]

Baricitinib

The drug that suppresses Janus kinase - Baricitinib - prevents a malfunction in the regulation of the production of inflammatory cytokines. In the United States, the drug is used as an emergency drug in combination with Remdesivir, when COVID-19 is suspected or confirmed in patients (children from the age of two and adults) who need additional oxygenation, invasive mechanical ventilation, or extracorporeal membrane oxygen therapy. [18]

Baricitinib together with Remdesivir is used when it is impossible to administer corticosteroids to non-intubated inpatients who need oxygen therapy. At the moment, drug monotherapy has not been approved. [19]

Local treatment protocols may differ from region to region and from country to country, so you should familiarize yourself with them before starting therapy. [20]

Interleukin-6 inhibiting drugs

Interleukin-6 inhibitors bind to receptors and inhibit impulse transmission. Interleukin-6 is a pro-inflammatory cytokine. With COVID-19-induced cytokine release syndrome, patients are recommended to test the administration of these medicines - in particular, Siltuximab, Tocilizumab. These drugs have received approval in a number of countries, but are classified as "off-label".

Experts in the UK recommend prescribing such drugs for adults who are critically ill in the intensive care unit with severe pneumonia and require respiratory support. This recommendation is based on proven information about a 24% decrease in mortality rates with the use of these IL-6 inhibitors throughout the day from the moment the patient is admitted to the IT hospital. A pronounced reduction in the period of intensive inpatient treatment was also found: a similar effect was successfully supplemented by the use of glucocorticosteroids. [21]

It is possible to prescribe a single dose of Tocilizumab in combination with Dexamethasone for persons requiring mechanical ventilation or high-flow oxygen therapy against a background of worsening respiratory failure. [22], [23]

Benefits of IL-6 inhibitors:

• reduce the risk of mechanical ventilation in inpatients;
• reduce mortality without increasing the risk of secondary infection (compared with standard therapy).

It is not recommended to administer IL-6 inhibitors to patients who do not require transfer to the IT department.

Interleukin-6 inhibitors are not included in all COVID-19 treatment protocols, so locally approved regimens should be used.

Ivermectin

An antiparasitic agent with a wide range of activity, Ivermectin, has been demonstrated to be effective against coronavirus infection using in vitro technology. However, the medication is currently under examination. [24], [25]

According to the results of a number of studies that have not yet received an expert assessment, contradictory facts were found:

• according to some data, taking Ivermectin does not have a clinically positive effect, and in some cases even worsens the course of the pathology;
• according to other data, against the background of Ivermectin, the symptomatic period and the duration of the excretion of the pathogen from the body are significantly reduced, inflammatory markers and mortality rates decrease.

To obtain clear and reliable results, more powerful and extensive clinical trials are currently being carried out, the course of which will be announced in the near future. [26]

Anakinra

An injectable (i / v, s / c) drug that inhibits interleukin-1 - Anakinra - is prescribed to patients in a test version for the treatment of COVID-19-induced cytokine release syndrome. The drug has received approval in many countries, but at the moment there is no complete evidence base for the effectiveness, safety and economic feasibility of treating patients with this drug with complications in the form of secondary hemophagocytic lymphohistiocytosis. [27]

A number of studies have shown a high survival rate for patients with acute respiratory distress syndrome and severe inflammation: they added Anakinra at high dosages to non-invasive mechanical ventilation and standard treatment with Hydroxychloroquine, Lopinavir / Ritonavir. There is evidence of a decrease in the need for invasive mechanical ventilation and a decrease in mortality in patients with a severe form of COVID-19 against the background of the use of Anakinra. [28], [29]

The drug can be beneficial in cytokine release syndrome, provided it is administered as early as possible. With a mild or moderate course of coronavirus infection, the use of Anakinra is impractical.

Immunoglobulin for intravenous administration

This is a biological blood product made on the basis of the plasma of healthy people. Immunoglobulin acts as an immunomodulator that suppresses an overly active immune response. The product has received approval in many countries, although its evidence base is considered somewhat limited (primarily due to lack of time). [30]

A retrospective analysis showed that the auxiliary use of intravenous immunoglobulin during the first 2 days after the patient is admitted to the hospital helps to reduce the need for mechanical ventilation and shorten the duration of treatment. [31]

Due to the lack of sufficient evidence, immunoglobulin cannot yet be considered a recommended agent: the decision to use it must comply with the accepted local therapeutic protocol. [32]

Stem cells

The study of the immunomodulatory activity of mesenchymal stem cells was actively started. Scientists believe that they can reduce the degree of damage to the respiratory system and suppress the process of cell-mediated immune inflammation. [33], [34]

Currently, mesenchymal stem cells from adult donors are being studied as a therapeutic biological product for moderate and severe acute distress syndrome in patients requiring mechanical ventilation. [35]

Interferons

Experts are discussing the possibility of using interferons with antiviral properties. Until a full evidence base is reached, it is not recommended to use interferons in patients with severe and critical form of COVID-19. [36]

At the moment, the following points are known:

• Interferon β-1a has not been particularly effective.
• Inhaled interferon β-1a has been shown to increase the chances of clinical optimization and accelerate recovery.
• Peginterferon λ showed a decrease in viral load and an increase in the frequency of negative nasopharyngeal smears on day 7 in patients with mild to moderate COVID-19.

Before using interferons, it is important to get advice in accordance with the treatment protocol of the respective region. [37], [38]

Vitamins

Some experts point to the feasibility of prescribing vitamin D supplements. Although the evidence base for this drug is extremely limited, it has been found meta-analytically that such supplements have the potential to reduce the severity of the disease. Higher doses of ergocalciferol significantly reduced the frequency of admission to the intensive care unit and helped to optimize the outcome of the disease. [39],  [40], [41]

Vitamin C supplementation generally has a positive effect on the course of viral pathologies. However, there is insufficient evidence for the effectiveness of ascorbic acid in severe and critical COVID-19. [42]

A randomized pilot project determined that intravenous injection of high doses of ascorbic acid potentially improves oxygenation and reduces mortality in critically ill patients. Nevertheless, this work is recognized as insufficiently complete. [43], [44]

Lopinavir / Ritonavir (oral protease inhibitors) [45]and Hydroxychloroquine / Chloroquine (antirheumatic anti-inflammatory and immunomodulatory agents) have not received sufficient evidence of efficacy . [46]WHO cannot recommend medicines with low or medium confidence in efficacy and safety.