With inputs from Dr Monica Vasudev

1002: Drug treatment – Remdesivir: The much sought-after results from the National Institute of Allergy and Infectious Diseases clinical trial of remdesivir, published in May, confirmed preliminary findings indicating that the drug reduces the disease course for hospitalized COVID-19 patients. The US Food and Drug Administration (FDA) issued an emergency use authorization for the drug. Drugmaker Gilead came out with results from the sponsored, randomized phase 3 SIMPLE trial, which suggested that a 5-day course of the drug led to improved outcomes among patients hospitalized with COVID-19 who did not require ventilation.

According to the National Institutes of Health, the most benefit was seen in patients on oxygen who did not require ventilation.

Dutch investigators; however, warned that the drug can be associated with rare but severe liver complications.

Take home message: Remdesivir is administered intravenously, thus restricting its use to hospitalized patients. Phase 1 trials of an inhaled nebulized version were started in late June 2020 to ascertain if remdesivir can be used on an outpatient basis and at earlier stages of disease.

The FDA has cautioned against use of the drug in combination with hydroxychloroquine (HCQ).

Dexamethasone

British researchers stated that the RECOVERY trial with more than 6000 patients had been stopped early owing to positive results. Dexamethasone was shown to reduce death rate by about one-third among severely ill hospitalized COVID-19 patients. There was a mixed reaction in the United States initially.

Some clinicians suggested that the results confirmed their own experience, while others were wary of embracing the study results prior to peer review.

The Infectious Diseases Society of America (IDSA) announced that the drug will be included in the COVID-19 treatment guidelines. Dexamethasone, or an equivalent steroid such as methylprednisolone or prednisone, is recommended for hospitalized patients requiring supplemental oxygen, mechanical ventilation, or extracorporeal mechanical oxygenation.

Take home message: Corticosteroids are not generally recommended for the treatment of COVID-19 or any viral pneumonia; however, the UK RECOVERY trial changed that. IDSA guidelines include low-dose dexamethasone (6 mg orally or intravenously daily for 10 days) in patients requiring respiratory support. The World Health Organization has warned clinicians to reserve the use for severely ill patients.

Hydroxychloroquine

As per, initial data, HCQ and chloroquine, sometimes in combination with azithromycin, had some level of efficacy in COVID-19 patients. However, newer data from observational trials soon followed, pointing that the drugs had no benefit and could also be dangerous for some patients. Following 2 months of controversy, the FDA revoked the emergency use authorization it had granted for use of these agents in inpatients.

In early July, the Henry Ford Hospital came out with the results of a retrospective, observational trial of HCQ with azithromycin that revealed that the combination, if given within the first 2 days of hospital admission, reduced COVID-19 mortality.

Trials of HCQ as preventive therapy are underway. A randomized trial published in early June noted that the drug was ineffective as prevention and the side effects were common.

Take home message: While some still promote its benefit, especially if given early in the course of infection, there is little evidence to support its use at any stage of illness.

Other Antimicrobials

Azithromycin. Some initial trials of azithromycin in combination with HCQ showed promise, but later results have not held up and major cardiology organizations have cautioned against the combination. There are no recommendations for use of azithromycin.

Antiviral agents. The UK-based RECOVERY trial looked into other drugs besides dexamethasone, and noted that the combination of lopinavir and ritonavir was not beneficial in hospitalized patients. A Japanese trial of favipiravir revealed that patients receiving the drug early in the trial had more improvement as compared to those given delayed doses; however, the results did not reach statistical significance.

Other Drugs

Convalescent plasma. A very small Chinese pilot study reported in April that its use in severely ill COVID-19 patients led to a rise in antibody titers, reduction in viral load, and improved the symptoms. Other studies have not yet shown it to be effective. The FDA has approved its use in patients with serious or immediately life-threatening infection.

Colchicine. An undergoing open-label, randomized trial in Greece has suggested that hospital course was slightly shorter and the time to clinical deterioration improved in patients treated with colchicine. There appeared to be no significant differences between treated and untreated groups in cardiac and inflammatory biomarkers.

Nitric oxide. In 2004, the role of inhaled nitric oxide was assessed as a supportive measure for patients with SARS-CoV-1. It reversed pulmonary hypertension, improved severe hypoxia, and decreased the length of ventilatory support. A phase 2 study is ongoing in patients with COVID-19, aimed at preventing disease progression in those with severe acute respiratory distress syndrome.

Zinc. Initial trials of HCQ often evaluated the drug in combination with azithromycin and zinc. Some studies pointed that zinc may be somewhat effective in treatment of upper respiratory infections, some of which are caused by coronaviruses; however, the National Academies of Sciences, Engineering, and Medicine warned that there is no evidence to suggest that it has a role in the treatment or prevention of COVID-19.

Monoclonal antibodies. Human antibodies are being investigated across the world. Eli Lilly has come out with positive interim results of its trials of monoclonal antibodies, and expects FDA review and possible approval by September. European trials of another antibody could begin soon. Trials of a third agent are expected to start in August in Singapore.

[Medscape Excerpts]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA