161 CMAAO CORONA FACTS and MYTH COVID Drugs Update
Dr K Aggarwal
With inputs from Dr Monica Vasudev
1002: Medscape Excerpts:
Much-anticipated results from the National Institute of Allergy and Infectious Diseases' clinical trial of remdesivir, published in May, confirmed preliminary results suggesting that the drug shortens the disease course for hospitalized COVID-19 patients. That earlier report resulted in the US Food and Drug Administration (FDA) issuing an emergency use authorization for the drug. Drugmaker Gilead subsequently released results from the sponsored, randomized phase 3 SIMPLE trial, which found that a 5-day course of the drug improved outcomes among patients hospitalized with COVID-19 who did not need ventilation.
The National Institutes of Health said that the most benefit was in patients on oxygen who did not require ventilation.
Dutch investigators have cautioned that it can be associated with rare but severe liver complications.
Take home message: Remdesivir is administered intravenously, limiting its use to hospitalized patients. However, phase 1 trials of an inhaled nebulized version were initiated in late June 2020 to determine whether remdesivir can be used on an outpatient basis and at earlier stages of disease.
The FDA has warned against use of remdesivir in combination with hydroxychloroquine (HCQ) .
British researchers that the RECOVERY trial involving over 6000 patients had been halted early due to positive results. The investigators reported that dexamethasone reduced death rates by about a third among severely ill hospitalized COVID-19 patients. Initial reaction in the United States was mixed.
While a number of clinicians indicated that the results confirmed their own experience, others were wary of embracing the study results prior to peer review.
Infectious Diseases Society of America (IDSA) announced that the drug will now be incorporated into COVID-19 treatment guidelines. Dexamethasone, or an equivalent steroid such as methylprednisolone or prednisone, is recommended for hospitalized patients who require supplemental oxygen, mechanical ventilation, or extracorporeal mechanical oxygenation.
Take home message: Corticosteroids are not generally recommended for treatment of COVID-19 or any viral pneumonia, 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. At present, the World Health Organization has cautioned clinicians to reserve use for severely ill patients.
Initial data suggested that HCQ and chloroquine, sometimes in combination with azithromycin, had some degree of efficacy in treating COVID-19. But those studies were rapidly followed by newer data from observational trials, suggesting that the drugs were not only without benefit but also could be dangerous in some patients. After 2 months of controversy, the FDA revoked the emergency use authorization it had previously granted for use of these agents in inpatient settings.
The matter seemed to be put to bed until early July when the Henry Ford Hospital released results of a retrospective, observational trial of HCQ with azithromycin that concluded that the combination, if given within the first 2 days of hospital admission, reduced COVID-19 mortality.
Trials of HCQ as preventive therapy are ongoing, though a randomized trial published in early June found that the drug was ineffective as prevention and that side effects were common.
Take home message: While some continue to tout its benefit, particularly if given early in the course of infection, there is little evidence at this time to support its use at any stage of illness.
Azithromycin. While some initial trials of azithromycin in combination with HCQ were promising, later results have not held up and major cardiology organizations now warn against the combination. There are no recommendations for use of this antimicrobial.
Antiviral agents. The UK-based RECOVERY trial examined other drugs in addition to dexamethasone, concluding that the combination of lopinavir and ritonavir had no benefit in hospitalized patients. A Japanese trial of favipiravir, determined that patients given the drug early in the trial showed more improvement than those who received delayed doses, but the results did not reach statistical significance.
Convalescent plasma. While a very small Chinese pilot study of convalescent plasma reported in April that its use in severely ill COVID-19 patients raised antibody titers, reduced viral load, and led to symptom improvement, 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 open-label, randomized trial currently underway in Greece has reported that hospital course was slightly shorter and the time to clinical deterioration improved in patients treated with colchicine, although there were no significant differences between treated and untreated groups in cardiac and inflammatory biomarkers.
Nitric oxide. Inhaled nitric oxide was studied as a supportive measure for patients with SARS-CoV-1 infection in 2004. It was found to reverse pulmonary hypertension, improve severe hypoxia, and shorten the length of ventilatory support. A phase 2 study is underway in patients with COVID-19, with the goal of preventing disease progression in those with severe acute respiratory distress syndrome.
Zinc. Initial trials of HCQ often studied it in combination with azithromycin and zinc. While some studies have suggested that zinc may be somewhat effective in treatment of upper respiratory infections, some of which are caused by coronaviruses, the National Academies of Sciences, Engineering, and Medicine cautions that there is no evidence to suggest that the supplement has a role in the treatment or prevention of COVID-19.
Monoclonal antibodies. The use of human antibodies is being investigated by a number of teams around the world. Eli Lilly has reported positive interim results of its trials of monoclonal antibodies, and anticipates FDA review and possible approval by September. European trials of another antibody could begin as early as this summer. And trials of a third agent are planning to start in August in Singapore.