Clinical Trials of Possible Coronavirus Treatments Underway

Effective therapies for the coronavirus are urgently needed. Since the identification of the 2019 coronavirus (2019-nCoV) in Wuhan, China, the virus has spread to dozens of countries and led to over 90,000 infections and 3,000 deaths worldwide. The virus-associated disease course, known as COVID-19, includes symptoms with varying severity from mild coughing to life-threatening organ dysfunction and acute respiratory distress syndrome. Currently, the virus is spreading in the United States, with two virus-associated deaths confirmed in Washington state and presumptive-positive cases in Washington, California, and Oregon. These cases are thought to have resulted from person-to-person community spread of the virus. Since current therapy is limited to supportive care, effective antiviral treatment strategies are critically important for saving the lives of individuals most susceptible to a severe disease course. Clinical trials of possible coronavirus treatments are currently underway.

While a vaccine against the virus is currently in development by multiple groups, non-vaccine treatment strategies are also being evaluated, including traditional medicines, small-molecule pharmacologic antiviral agents, and immune-boosting compounds, including monoclonal antibodies and intravenous hyperimmune globulin isolated from individuals that have been exposed to the virus. In a recent publication, the Director of the CDC and other leading federal scientists stated that they “anticipate that the first candidates will enter phase 1 trials by early spring” and that the virus would likely continue to spread. “Given the efficiency of transmission as indicated in the current report, we should be prepared for Covid-19 to gain a foothold throughout the world, including in the United States,” the authors stated.

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According to a recent article by Dr. Erik de Clercq, a Belgian physician and virologist that co-discovered the important anti-viral agent Tenofovir, and Dr. Guangdi Li, improved treatment strategies for coronavirus infection may include existing antiviral agents instead of novel vaccines or compounds. “No drug or vaccine has yet been approved to treat human coronavirus” and “new interventions are likely to require months to years to develop,” stated Clercq and Li.

Since proteins produced by 2019-nCoV and essential to the life cycle of the virus share important structural and sequence similarities to those of other viruses within the coronavirus family, including the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses, existing MERS and SARS anti-viral agents could be repurposed to battle 2019-nCoV. Pharmacologic agents Favipiravir and Ribavirin, which block synthesis of viral RNA and therefore reproduction of the virus, may show efficacy for the treating the disease. Clinical trials evaluating Favipiravir in combination with the immune-boosting compound interferon-alpha or the influenza inhibitor baloxavir marboxil are currently underway.

Another drug, Remdesivir, which has a structure similar to the HIV inhibitor Tenofovir, has shown efficacy against the 2019 coronavirus in vitro. The recovery of an infected US patient, who received intravenous infusions of Remdesivir, may be attributable to the drug. Two phase III trials evaluating the efficacy of intravenous Remdesivir for the treatment of the coronavirus were initiated in February and are anticipated to be completed by April 2020.

A recent publication describing the treatment of 138 coronavirus patients in Wuhan, China, has provided preliminary information on the outcomes of patients treated with existing clinical interventions. Among the 138 patients, at the time of the publication, 85 were hospitalized, 6 had died, and 36 were admitted to the intensive care unit (ICU). Most patients received glucocorticoid therapy, antiviral therapy with the anti-influenza drug oseltamivir, and anti-bacterial therapy with multiple agents. Among the 11 patients remaining the ICU, all received ventilation. There was a relatively high incidence of life-threatening complications among the 138 patient cohort. 12 experienced shock (8.7%), 27 acute respiratory distress syndrome (19.6%), 10 acute cardiac injury (7.2%), and 23 arrhythmia (16.7%).

The virus is thought to spread via respiratory droplets when patients open their mouth to sneeze, talk, or cough, or via close contact with the mouth, eyes, nose, or hands of infected individuals. This is supported by recent research which suggests that, early in the disease course and prior to the onset of significant symptoms, the virus is present at high levels within and near the tongue and tonsils. Currently, infected individuals are likely to spread the virus on average to 2.2 other people with the elderly and immunosuppressed more susceptible to severe cases of infection.

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Preventative action by the general public may contribute to halting the spread of the disease. Of note, the CDC has provided recommendations for preventing the spread of the coronavirus. Sick individuals should remain at home instead of traveling to work or school. The nose and mouth should be covered with a tissue when coughing or sneezing, and the tissue should be thrown away afterwards. Hands should be washed frequently with soap and water or an alcohol-based hand rub with at least 60% alcohol, and potentially contaminated surfaces and objects disinfected and cleaned with regular household wipes or cleaning spray.

Although the CDC is deciding on a case-by-case basis when to release infected individuals from isolation, the following criteria are currently being used: (1) the absence of fever without fever-reducing medications; (2) the absence of symptoms including coughing; (3) at least two respiratory specimens testing negative for the virus with at least 24 hours between the collection of each sample.

In addition, although the physical and chemical properties of the coronavirus are not yet clear, researchers believe that coronaviruses are sensitive to ultraviolet light and heat. Previous studies have shown that these viruses can be inactivated by heating at 56 degrees celsius (133 degrees fahrenheit) for 30 minutes and by the use of lipid solvents such as 75% ethanol and disinfectants that contain chlorine. However, the CDC states that “it is not yet known whether weather and temperature impact the spread of COVID-19. Some other viruses, like the common cold and flu, spread more during cold weather months but that does not mean it is impossible to become sick with these viruses during other months.  At this time, it is not known whether the spread of COVID-19 will decrease when weather becomes warmer.  There is much more to learn about the transmissibility, severity, and other features associated with COVID-19 and investigations are ongoing.”

Clercq ED, Li G. (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00016-0

Huang C, Wang Y, Li X, et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395, 497-506.