Interferon Flops for Severe COVID

Hospitalized patients with COVID-19 pneumonia recovered no faster when treated with interferon beta-1a and remdesivir (Veklury) as when treated with remdesivir alone, data from the phase III ACTT-3 trial found.

In the National Institute of Allergy and Infectious Diseases trial, patients in both groups had a mean 5 days to recovery (RR 0.99, 95% CI 0.88-1.13), and there was no significant difference in mortality rates either (5% for interferon group vs 3% for remdesivir alone, HR 1.33, 95% CI 0.69-2.55), reported Andre Kalil, MD, of the University of Nebraska Medical Center in Omaha, and colleagues, writing in Lancet Respiratory Medicine.

While they noted that prior research found that interferon may improve COVID-19 outcomes, the drug showed no survival benefit in the WHO SOLIDARITY trial. Also, the NIH COVID-19 guidelines recommend against its use for patients with severe COVID, outside of a clinical trial.

This stage of the Adaptive COVID-19 Treatment Trial involved 63 sites globally, 56 of which were in the U.S. Participants were adults with laboratory-confirmed COVID-19, who had radiographic infiltrates on imaging, an oxygen saturation on room air of 94% or less, or needed supplemental oxygen. They were randomized 1:1 to receive remdesivir for up to 10 days, and up to four doses of either subcutaneous interferon beta-1a or placebo every other day.

From Aug. 5 to Nov. 11, 2020, 487 patients were randomized to the intervention and 452 to the control group, though the authors noted that after September 4, the trial no longer accepted patients with ordinal scores of 6. Of the 452 patients, 448 had an ordinal score of 4 or 5, and 35 had an ordinal score of 6 at baseline due to Data Safety and Monitoring Board concerns about an increase in severe adverse events for this group.

Mean age was about 59; 58% were men and 60% were white. Nearly all patients in both groups had at least one comorbidity at baseline (89%-90%). Median duration of illness was about 9 days in both groups.

There was no difference in time to improvement by 1-2 points on the ordinal scale, time to discharge, or number of days requiring supplemental oxygen, the authors noted. In addition, they said there was no difference between groups in the proportion of patients needing mechanical ventilation among patients with an ordinal scale of 4 or 5 at baseline.

Twenty-one patients in the intervention group and 16 in the controls died during the 28-day follow-up. Kaplan-Meier estimates of mortality post-28 days randomization were 5% (95% CI 3-7) in the interferon beta-1a plus remdesivir group and 3% (95% CI 2-6) in the placebo plus remdesivir group, according to the authors. The most common grade 3 or 4 adverse event in both groups was decreased lymphocyte count (7% each).

Kalil’s group hypothesized about why the ACTT-3 results might be different compared to the previous trials. They wrote that “the mechanism of interferon is to decrease viral replication,” but since it was administered with antiviral remdesivir, there may not have been “additional antiviral effects,” they noted. Trial designs were also different, with prior trials enrolling patients with milder illness.

Nevertheless, they considered their results definitive when comparing them to smaller studies.

“Although our results contrast those of other observational studies and [randomized] trials, considering the size and design of ACTT-3, it is unlikely that subcutaneous interferon beta-1a shows efficacy in patients [hospitalized] with COVID-19,” the authors wrote.