MIMS Respirology 2020.10.26
More than 9 months into the combat against COVID-19, the world has seen battles being stepped up on all fronts in the search for an effective therapy. While new drugs are being developed, old drugs are repurposed as potential treatment for COVID-19, and a plethora others are upcoming in the pipeline.
Global efforts are also ongoing to better understand the type of patients who are most likely to benefit from a therapy and the disease stage such therapy should be given.
With the release of data from recent large-scale phase III studies, steroids and remdesivir are two old and new drugs, respectively, to gain footing as recommended therapies in international guidelines for COVID-19.
The old: Steroids back on the front burner
Giving inexpensive, readily available corticosteroid drugs to patients critically ill with COVID-19 led to improved outcomes and could even be lifesaving, multiple related studies have shown.
Critically ill patients treated with systemic corticosteroids had 34 percent lower risk of all-cause mortality over 28 days compared with those on usual care or placebo (summary odds ratio [OR], 0.66; p<0.001), reveals a prospective meta-analysis of seven randomized clinical trials (RCTs). [JAMA 2020;324:1330-1341]
“These studies provide evidence and some hope that an effective, inexpensive, and safe treatment has been identified. Hope because corticosteroids provide a widely available treatment for the most severely ill patients with COVID-19,” wrote Drs Hallie Prescott and Todd Rice from the University of Michigan, Ann Arbor, Virginia and Vanderbilt University, Nashville, Tennessee, US, respectively, in a linked editorial. [JAMA 2020;324:1292-1295]
Based on the data from the meta-analysis, the WHO* has issued a Living Guidance recommending systemic corticosteroids as the standard of care for COVID-19 patients with severe and critical illness. [https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1. Accessed 15 Oct 2020]
However, the use of steroids in patients with non-severe COVID-19 was discouraged, as “current data indicated they would not likely derive benefit and may derive harm … [Moreover,] indiscriminate use of any therapy for COVID-19 would potentially rapidly deplete global resources and deprive patients who may benefit from it most as potentially life-saving therapy,” wrote the WHO panel.
The first evidence that steroids might yield survival benefit to patients with severe COVID-19 came from the RECOVERY** trial, which showed that dexamethasone reduced deaths by one-third in patients requiring invasive mechanical ventilation (rate ratio [RR], 0.64) and by one-fifth in those receiving oxygen without invasive ventilation (RR, 0.82) compared with usual care alone. [N Engl J Med 2020;doi:10.1056/NEJMoa2021436]
Prior to this, clinicians had been reluctant to use steroids for treating severe COVID-19 due to concerns of side effects and a lack of direct strong evidence supporting its use.
“The signal seen in this trial led most ongoing trials of corticosteroids to suspend recruitment … because equipoise for withholding corticosteroids was no longer present,” noted the researchers of the meta-analysis, which included RECOVERY as one of the seven RCTs.
Among the trials being suspended were three RCTs — CoDEX, REMAP-CAP, CAPE COVID*** — which were also published simultaneously in JAMA and included in the meta-analysis.
The CoDEX study showed that adding dexamethasone to usual care significantly increased the number of days patients were alive without requiring mechanical ventilation compared with usual care alone over 28 days (mean, 6.6 vs 4.0 days; p=0.04). Participants were COVID-19 patients in ICUs with moderate-to-severe ARDS#. The dexamethasone arm received 20 mg of the drug intravenously once daily for 5 days, followed by a daily dose of 10 mg for another 5 days or until ICU discharge, in addition to usual care. [JAMA 2020;324:1307-1316]
Similarly, patients with severe COVID-19 who received hydrocortisone in the REMAP-CAP trial were more likely to survive without needing respiratory or cardiovascular support in the ICUs over 21 days than those who did not receive hydrocortisone. Hydrocortisone was given as a 7-day, fixed-dose course intravenously (50 mg or 100 mg every 6 hours) or based on appearance of shock. [JAMA 2020;324:1317-1329]
In CAPE COVID, another RCTs of hydrocortisone, the rate of treatment failure was lower in the hydrocortisone arm than the placebo arm (42.1 percent vs 50.7 percent; p=0.29), although the difference between groups was not statistically significant. The trial enrolled critically ill patients with COVID-19-related acute respiratory failure in the ICUs. [JAMA 2020;324:1298-1306]
“The publication of these three RCTs of corticosteroids and the prospective meta-analysis in this issue of JAMA represents an important step forward in the treatment of patients with COVID-19,” Prescott and Rice highlighted.
“These trials and the meta-analysis have strengthened confidence, further defined the benefit [beyond the RECOVERY trial], and shifted usual care of COVID-19–related ARDS to include corticosteroids,” they added.
“The consistent findings of benefit in these studies provide definitive data that corticosteroids should be first-line treatment for critically ill patients with COVID-19,” the editorialists stated.
In view of these findings, the NIH## has recently updated its treatment guidelines to include dexamethasone with or without remdesivir for hospitalized patients requiring high-flow oxygen or invasive ventilation.
Echoing the recommendations of the WHO, the NIH panel also recommended against using dexamethasone for non-hospitalized COVID-19 patients or who are hospitalized with moderate illness but do not require oxygen supplementation.
Based on these developments, the Singapore National Centre for Infectious Diseases (NCID) has also updated its treatment guidelines to recommending dexamethasone for patients with severe COVID-19 who require supplemental oxygen or mechanical ventilation.
The new: Remdesivir speeds up recovery
Following the positive preliminary results at day 15 released earlier, the latest final report of the ACTT-1### trial at day 29 further upholds the efficacy of remdesivir in speeding recovery. [N Engl J Med 2020;doi:10.1056/NEJMoa2007764]
Over 29 days of follow-up, the addition of a 10-day course of remdesivir significantly shortened recovery time by 5 days compared with usual care alone in hospitalized COVID-19 patients with lower respiratory tract infection (median, 10 vs 15 days; RR, 1.29; p<0.001).
The benefit was most prominent in patients requiring supplemental oxygen (baseline ordinal score of 5; median, 7 vs 9 days; RR, 1.45, 95 percent confidence interval [CI], 1.18–1.79).
Remdesivir-treated patients were also 50 percent more likely to experience clinical improvement by day 15 than those on usual care alone (OR, 1.5; 95 percent CI, 1.2–1.9), based on the eight-category ordinal scale.
In addition, death rates trended lower with remdesivir vs usual care alone at day 15 (hazard ratio [HR], 0.55; 95 percent CI, 0.36–0.83) and day 29 (HR, 0.73, 95 percent CI, 0.52–1.03).
Again, stratifying the analysis by patients’ baseline clinical status showed that the greatest survival benefit was in those requiring supplemental oxygen, with a statistically significant reduction in mortality risk by 72 percent at day 15 and by 70 percent at day 29.
“Based on clinical experience, we have seen that patient response and mortality risk differ across the disease spectrum. With this mortality subgroup post hoc analysis, we now have data suggesting that giving remdesivir to patients on oxygen may significantly reduce their chances of death as compared to other subgroups,” said ACTT-1 co-investigator Professor Andre Kalil from the University of Nebraska Medical Center in Omaha, Nebraska, US.
“These data provide clinicians with important information to help optimize patient care,” he said.
Remdesivir is currently recommended by the NIH panel as the first-line treatment for hospitalized COVID-19 patients requiring supplemental oxygen.
“Given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient for all patients,” the ACTT-1 investigators pointed out, noting that studies are ongoing to evaluate remdesivir in combination with immune response modifiers.
The upcoming: Antibodies as potential treatment?
Monoclonal antibodies have been thrust into the limelight since the COVID-19 treatment regimen for US President Donald Trump was made known. The said treatment included the antibody cocktail REGN-COV2 as part of the regimen, amongst dexamethasone and remdesivir.
Though still in experimental stage, preliminary data showed that the antibody cocktail reduced viral load and associated symptoms compared with standard care alone in nonhospitalized COVID-19 patients.
“The greatest treatment benefit was in patients who had not mounted their own effective immune response,” said investigators in a company statement.
Other antibodies under investigation include gimsilumab and tocilizumab, which tackle the inflammatory pathways one way or the other.
Where do we stand now?
While medical science has come a long way in the search for a remedy against COVID-19 since the first day the virus was discovered, no therapy exists yet that has been proven to treat all patients with COVID-19.
With its wide disease spectrum seen — from mild to critical illness — it is likely that different disease stages would call for different treatment strategies. Also, combination rather than lone therapies might be required in certain circumstances.
Meanwhile, remdesivir has just been approved by the US FDA in October for COVID-19 patients requiring hospitalization. Nonetheless, not one drug currently fits as a magic bullet against the disease. The old, the new, and the upcoming therapies are merely pieces of that one giant puzzle.