Remdesivir, another potential therapy for Patients with Severe COVID-19
Some people afflicted with COVID-19 show no obvious symptoms of the disease, whilst a minority can develop pneumonia and life-threatening complications, including acute respiratory distress syndrome (ARDS), multisystem organ failure, and ultimately, death. Old age alone is an important risk factor for COVID-19, and older patients and those with pre-existing respiratory or cardiovascular conditions are at the greatest risk for severe complications. In the absence of a proven effective therapy, current management consists of supportive care, including invasive and non-invasive oxygen support and treatment with antibiotics. Many patients have received off-label or compassionate-use therapies such as anti-retrovirals, anti-parasitic agents, anti-inflammatory compounds, and convalescent plasma (plasmapheresis).
Remdesivir is a newly developed drug which has broad range activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERSCoV]). Scientists have tested remdesivir in the laboratory and have observed that the drug has activity against SARS-CoV-2. In addition, remdesivir appears to have a favorable clinical safety profile, as reported on the basis of experience in approximately 500 people, including healthy volunteers and patients treated for acute Ebola virus infection.
In a recent paper, Grein and colleagues (2020) report outcomes in a cohort of patients hospitalized for severe COVID-19 who were treated with remdesivir on a compassionate-use basis. The patients received a 10-day course of remdesivir and clinical improvement was observed in 36 of 53 patients (68%). This early report is the first to demonstrate efficacy in a small cohort of patients who were severely ill with COVID-19 and treated with remdesivir. It is expected that additional data from ongoing randomized, controlled trials will add to the evidence on the safety and efficacy of remdesivir for COVID-19.
Effectiveness of convalescent plasma therapy in severe COVID-19 patients
Convalescent plasma (CP) therapy has been administered as an adaptive immunotherapy for the prevention and treatment of many infectious diseases for over a century. Over the past two decades, CP therapy was successfully used in the treatment of SARS, MERS, and the 2009 H1N1 pandemic with satisfactory efficacy and safety. A meta-analysis from 32 studies on SARS coronavirus infection and severe influenza showed a statistically significant reduction in the pooled odds of mortality following CP therapy, compared with placebo or no therapy. Patients who have recovered from COVID-19 with a high neutralizing antibody titre may be a valuable donor source of CP. Nevertheless, the potential clinical benefit and risk associated with convalescent blood products in COVID-19 remain unproven. Duan and colleagues (2020) have now performed a pilot study in three participating hospitals to explore the feasibility and efficacy of CP treatment in 10 patients suffering from severe form of COVID-19.
After CP transfusion, the authors observed that the level of neutralizing antibody increased rapidly in five cases, while that of the remaining cases was maintained at a high level. Several clinical parameters tended to improve as compared to pretransfusion. The viral load was undetectable after transfusion in seven patients who previously had the virus. No severe adverse effects were observed.
The first key factor associated with CP therapy is the neutralizing antibody titre. To find eligible donors who have high levels of neutralizing antibody is a prerequisite. Some studies have reported that the level of specific neutralizing antibody to SARS-CoV decreases gradually 4 months after the disease process, reaching undetectable levels in patients at 36 months after disease status. These data suggest that the neutralizing antibodies represent short-lasting humoral immune response, and plasma from recently recovered patients should be more effective.
The second key factor associated with efficacy of CP is the treatment time point. A better treatment outcome was observed among SARS patients who were given CP before 14 days (highlighting the importance of timely rescue therapy. One of the risks of plasma transfusion is the transmission of the potential pathogen. Methylene blue photochemistry was applied in this study to inactivate the potential residual virus and to maintain the activity of neutralizing antibodies as much as possible, a method known to be much better than ultraviolet (UV) C light.
The preliminary results of this trial appear promising, justifying a randomized controlled clinical trial in a larger patient cohort. In conclusion, this pilot study on CP therapy shows a potential therapeutic effect and low risk in the treatment of severe COVID-19 patients. One dose of CP with a high concentration of neutralizing antibodies can rapidly reduce the viral load and improve clinical outcomes. The optimal dose and treatment time point, as well as the definite clinical benefits of CP therapy, need to be further investigated in randomized clinical studies.
Prepared by:
Dr Reshma Ramracheya
Research Scientist & University Research Lecturer at the University of Oxford
Senior Research Fellow at Wolfson College, University of Oxford
Reshma.ramracheya@ocdem.ox.ac.uk
