Current and emerging treatment options for patients with COVID-19

The pandemic spread of the COVID-19 infection has had a major impact on the global healthcare system. Many experts have been forced to suspend some ongoing research in favor of developing and testing new drugs to treat coronavirus patients. The main task of scientists has become the selection of existing and creation of new effective drugs at the same time as creating a clear evidence base for their positive effect.

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

Remdesivir

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

European and English specialists have allowed the drug to be used in children aged 12 and over, weighing over 40 kg, as well as in adults with pneumonia and the need for oxygen therapy. In the United States, the requirements for prescribing Remdesivir are the same, including emergency care for pediatric patients.

However, WHO does not approve the use of Remdesivir in hospitalized patients as an additional component of the standard therapeutic regimen, regardless of the severity of the pathology. This is due to the lack of effect of the drug on reducing the mortality rate from COVID-19, or on the early disappearance of symptoms of the disease, compared with standard therapy. [ 1 ]

The opinion of the representatives of the National Institutes of Health of the United States is as follows:

• Remdesivir is indicated for independent use (in patients with minimal need for oxygen therapy) or in combination with Dexamethasone (in patients requiring additional oxygenation).
• The use of Remdesivir in combination with Dexamethasone is recommended for patients who require 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.
• Remdesivir may be prescribed to patients who do not require oxygen therapy but who are prone to progression of the pathology.
• It is recommended to use Remdesivir for 5 days (or until discharge from the hospital, if it occurs earlier). It is allowed to extend the treatment course up to 10 days (in the absence of significant clinical improvement).
• The drug should not be used routinely for inpatient treatment of patients who do not require oxygenation, with oxygen saturation values greater than 94%.

Due to conflicting recommendations, regionally specific guidelines for the treatment of COVID-19 should be consulted before using this medicine.

Imdevimab / Casirivimab (REGN-COV2)

The intravenous drug, a mixture of human immunoglobulin G-1 antibodies active against the COVID-19 pathogen, is undergoing further research. However, in American clinics, the drug is approved as an emergency treatment for mild to moderate coronavirus infection in adults and children. The UK and European countries have not yet approved REGN-COV2, but the European Pharmaceutical Agency continues to study the material within the framework of clinical trials.

Interim studies have shown that Imdevimab/Casirivimab reduces viral load from baseline to day 7, primarily in patients with an immature immune response or with a high baseline viral load. [ 2 ]

The drug has been shown to be ineffective when used in hospitalized patients or in patients requiring oxygenation. The possibility of prescribing the drug in cases where oxygenation is not required or in patients who require low-flow oxygen therapy is being investigated.

The drug was shown to successfully neutralize circulating B.1.1.7 and B.1.351 types of SARS-CoV-2.

Data have been published on the positive use of neutralizing monoclonal antibodies to prevent the disease in people who have had household contact with COVID-19 patients: according to the study, passive vaccination with REGN-COV2 prevented symptomatic pathology in 100% of cases and halved the overall rates of symptomatic and asymptomatic infection.

Before prescribing a drug, it is imperative to familiarize yourself with the specifics of the local treatment protocol.

Bamlanivimab

Another representative of intravenous neutralizing monoclonal antibodies, Bamlanivimab (LY-CoV555), is in the research stage. American experts have already approved the emergency use of the drug in therapeutic regimens for mild and moderate COVID-19 in children and adults. Other countries have not yet received approval. [ 3 ]

According to the recommendations of American specialists, the use of Bamlanivimab may be indicated for patients with an increased risk of worsening pathology. Contraindications include severe COVID-19, late stage of the disease, as well as everyday outpatient practice.

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

According to the results of the BLAZE-2 study, the drug reduces the likelihood of infection in the home (nursing home) by 80%. [ 4 ]

The drug is undergoing another stage of research, so it cannot be recommended for widespread use: it is necessary to focus on local treatment protocols.

Convalescent plasma

Blood serum from people who have recovered from COVID-19 is a biomaterial that contains ready-made antibodies. This drug is allowed to be used as emergency aid for patients in inpatient departments of American clinics. Other countries continue to study the drug, considering the information about it insufficient.

According to the latest data, convalescent plasma reduces the mortality rate of hospitalized COVID patients by 9% (if prescribed within three days after diagnosis) or by 12% (if prescribed on the 4th day or more). There is information on an increase in viral clearance and an increase in clinical improvement rates as a result of using convalescent plasma. The positive effect of early administration of the drug on reducing the progression of the pathology and inhibiting its transformation into a severe form has been proven. [ 5 ]

Additional studies are currently being conducted to assess the safety and efficacy of convalescent serum. [ 6 ]

Baricitinib

The Janus kinase inhibitor Baricitinib prevents the disruption of inflammatory cytokine production regulation. In the United States, the drug is used as an emergency treatment in combination with Remdesivir, in cases of suspected or confirmed COVID-19 in patients (children from the age of two and adults) who require additional oxygenation, invasive mechanical ventilation or extracorporeal membrane oxygen therapy.

Baricitinib is used in combination with remdesivir when corticosteroids cannot be administered to hospitalized non-intubated patients who require oxygen therapy. Monotherapy with the drug is not currently approved. [ 7 ]

Local treatment protocols may vary from region to region and country to country, so please review these in detail before starting therapy. [ 8 ]

Interleukin-6 inhibitory drugs

Interleukin-6 inhibitors bind to receptors and inhibit impulse transmission. Interleukin-6 is a pro-inflammatory cytokine. In COVID-19-induced cytokine release syndrome, patients are recommended to undergo a trial administration of these drugs - in particular, Siltuximab, Tocilizumab. Such drugs have received approval in a number of countries, but are on the "off-label" list.

UK experts recommend prescribing such drugs to adult patients who are in critical condition in the intensive care unit with severe pneumonia and require respiratory support. This recommendation is based on proven information about a 24% reduction in mortality rates with the use of these IL-6 inhibitors within 24 hours from the moment the patient is admitted to the intensive care unit. A significant reduction in the period of inpatient intensive care has also been found: such an effect is successfully supplemented by the use of glucocorticosteroids. [ 9 ]

A single dose of Tocilizumab in combination with Dexamethasone may be administered to individuals requiring mechanical ventilation or high-flow oxygen therapy due to worsening respiratory failure. [ 10 ], [ 11 ]

Benefits of IL-6 inhibitors:

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

Administration of IL-6 inhibitors to patients who do not require transfer to the intensive care unit is not recommended.

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

Ivermectin

The broad-spectrum antiparasitic drug Ivermectin has demonstrated efficacy against coronavirus infection using in vitro technology. However, the drug is currently undergoing further testing.

A number of studies, which have not yet been assessed by experts, have revealed contradictory facts:

• 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 elimination of the pathogen from the body are significantly reduced, inflammatory markers and mortality rates are reduced.

To obtain clear and reliable results, more powerful and extensive clinical trials are currently being conducted, the progress of which will be made public in the near future. [ 12 ]

Anakinra

An injectable (IV, SC) 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 efficacy, safety and economic feasibility of treating patients with a complication in the form of secondary hemophagocytic lymphohistiocytosis with this drug.

A number of studies have found a higher survival rate in patients with acute respiratory distress syndrome and severe inflammation: they were given Anakinra in higher doses to non-invasive mechanical ventilation and standard treatment with Hydroxychloroquine, Lopinavir/Ritonavir. There is evidence of a reduced need for invasive mechanical ventilation and a decrease in mortality in patients with severe COVID-19 with the use of Anakinra.

The drug may be beneficial in cytokine release syndrome if administered as early as possible. In mild to moderate cases of coronavirus infection, the use of Anakinra is not advisable.

Immunoglobulin for intravenous administration

This is a blood bioproduct made from the plasma of healthy people. Immunoglobulin acts as an immunomodulator, suppressing an overactive immune response. The product has received approval in many countries, although its evidence base is considered somewhat limited (primarily due to lack of time). [ 13 ]

A retrospective analysis demonstrated that the adjunctive use of intravenous immunoglobulin during the first 2 days after hospitalization helps to reduce the need for mechanical ventilation and shorten the treatment period. [ 14 ]

Due to the lack of sufficient evidence, immunoglobulin cannot yet be considered a recommended treatment: the decision on its use should be in accordance with the accepted local therapeutic protocol. [ 15 ]

Stem cells

The study of the immunomodulatory activity of mesenchymal stem cells has begun actively. Scientists believe that they are capable of reducing the degree of damage to the respiratory system and suppressing the process of cell-mediated immune inflammation. [ 16 ]

Currently, mesenchymal stem cells from adult donors are being studied as a therapeutic biopreparation for moderate to severe acute distress syndrome in patients requiring mechanical ventilation. [ 17 ]

Interferons

Experts are discussing the possibility of using interferons with antiviral properties. Until a full evidence base is achieved, it is not recommended to use interferons in patients with severe and critical forms of COVID-19. [ 18 ]

At the moment the following points are known:

• Interferon β-1a has not shown particular efficacy.
• 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 swabs on day 7 in patients with mild to moderate COVID-19.

Before using interferons, it is important to obtain advice in accordance with the treatment protocol of the relevant region.

Vitamins

Some experts point to the advisability of prescribing vitamin D supplements. Although the evidence base for this drug is extremely limited, meta-analytics have shown that such supplements have the potential to reduce the severity of the disease. Higher doses of ergocalciferol significantly reduced the frequency of intensive care unit admissions and helped optimize disease outcome. [ 19 ]

Vitamin C supplements generally have a positive effect on the course of viral pathologies. However, there is insufficient evidence on the effectiveness of ascorbic acid in severe and critical forms of COVID-19. [ 20 ]

A pilot randomized trial found that IV injection of high doses of ascorbic acid potentially improves oxygenation and reduces mortality in critically ill patients. However, this work was considered to be of poor quality.[ 21 ],[ 22 ]

There is insufficient evidence of efficacy for drugs such as Lopinavir/Ritonavir (oral protease inhibitors) and Hydroxychloroquine/Chloroquine (antirheumatic anti-inflammatory and immunomodulatory drugs). [ 23 ] WHO cannot recommend the use of drugs with low or moderate evidence of efficacy and safety.