Adding interferon beta-1a to remdesivir did not speed up recovery in COVID-19

Adding interferon beta-1a to remdesivir did not hasten time to recovery among adults hospitalized with COVID-19, according to results of the phase III ACTT*-3 trial.

“The results of our study suggest that interferon beta-1a plus remdesivir is not associated with clinical benefit compared with remdesivir alone in hospitalized patients with COVID-19,” said the authors.

“Given the absence of benefit, subcutaneous interferon beta-1a treatment is not advised for patients hospitalized with COVID-19,” they said.

The double-blind study, conducted in 63 hospitals in Japan, Mexico, Singapore, South Korea, and the US, involved 969 individuals aged ≥18 years (mean age 58.7 years, 58 percent male, 60 percent White) hospitalized with RT-PCR–confirmed SARS-CoV-2 and ≥1 criteria for lower respiratory tract infection**. They were randomized 1:1 to receive intravenous remdesivir (200 mg loading dose on day 1 followed by 100 mg/day maintenance dose up to day 9 [unmasked]) and ≤4 subcutaneous doses of 44 μg interferon beta-1a or placebo every other day, in addition to standard (non-experimental) supportive care.

Mean duration of symptoms prior to enrolment was 8.7 and 8.5 days in the interferon beta-1a-remdesivir and placebo-remdesivir groups, respectively. Fifty percent of patients were aged 40–64 years, while 38 percent were aged ≥65 years. Ninety percent of patients had comorbidities at baseline, with 68 percent having ≥2 comorbidities. The most common were hypertension, obesity, and type 2 diabetes (58, 58, and 37 percent, respectively). The mean BMI was 33 kg/m². Seventy-seven percent had an ordinal score of 5 at enrolment.

Time to recovery within 28 days (the first day a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale used in previous ACTT trials) did not differ between patients who received interferon beta-1a-remdesivir and placebo-remdesivir (median 5 days in both groups; rate ratio, 0.99, 95 percent confidence interval [CI], 0.87–1.13; p=0.88). [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00384-2]

“There were no subgroups in which interferon beta-1a appeared to have benefit over placebo,” the authors noted.

Clinical improvement at 14 days was also not different between the interferon beta-1a-remdesivir and placebo-remdesivir groups (odds ratio, 1.01, 95 percent CI, 0.79–1.28; p=0.95).

Estimated mortality at 28 days also did not significantly differ between patients in the interferon beta-1a-remdesivir and placebo-remdesivir groups (5 percent vs 3 percent; hazard ratio [HR], 1.33, 95 percent CI, 0.69–2.55; p=0.39).

Among individuals with an ordinal score of 4 or 5 at baseline, grade 3–4 adverse events (AEs) occurred in 39 and 32 percent of interferon beta-1a-remdesivir and placebo-remdesivir recipients, respectively, and serious AEs in 15 and 13 percent, respectively. The most frequently occurring non-serious grade 3–4 AE was decreased lymphocyte count (7 percent in each group), and the most common serious AEs respiratory, thoracic, and mediastinal disorders. Eight percent of each group experienced a respiratory AE which included respiratory failure, acute respiratory failure, hypoxia, dyspnoea, or respiratory distress.

Among patients who did not require high-flow oxygen at baseline, those who received interferon beta-1a-remdesivir were more likely to experience AEs than those who received placebo-remdesivir (7 percent vs 3 percent).

 

Findings in patients with more severe disease

The study initially included patients with an ordinal score of 4–6, though this was later modified to exclude patients with an ordinal score of 6 (patients requiring non-invasive ventilation or use of high-flow oxygen devices) due to more severe AEs in these patients, leaving only 69 of these patients in the analysis.

Patients with a baseline ordinal score of 6 who were assigned interferon beta-1a-remdesivir were older and had more comorbidities associated with severe disease than those in the placebo-remdesivir group.

Estimated mortality at 28 days was 21 and 12 percent among interferon beta-1a-remdesivir and placebo-remdesivir recipients, respectively (HR, 1.74; p=0.38).

In this group, grade 3–4 AEs occurred in 60 and 36 percent of interferon beta-1a-remdesivir and placebo-remdesivir recipients, respectively, and serious AEs in 60 and 24 percent, respectively, though none of the serious AEs were considered related to the trial drugs.

The most common non-serious grade 3–4 AEs were decreased lymphocyte count (9 percent vs 18 percent), decreased haemoglobin concentration (11 percent vs 6 percent), decreased eGFR*** (11 percent vs 3 percent), acute kidney injury (3 percent vs 12 percent), deep vein thrombosis (9 percent vs 0), and decreased blood albumin concentration (6 percent vs 0). Fifty-four and 21 percent of interferon beta-1a-remdesivir and placebo-remdesivir recipients, respectively, experienced a respiratory AE.

“It is possible that interferon beta-1a could have increased the inflammatory response, leading to more severe respiratory disease in these patients. However, it is also possible that this worse outcome was influenced by baseline imbalances between the interferon beta-1a plus remdesivir and placebo plus remdesivir groups,” the authors said.

 

Different population/study design=different outcomes?

According to the authors, one potential reason behind the lack of effect in this trial is that interferon may not have had additional antiviral effects to those conferred by remdesivir.

Nonetheless, the results do not apply to patients with mild or early-stage disease or those who did not require hospitalization. The findings also do not reflect the effect of interferon beta-1a without the concomitant use of steroids, or if interferon was administered via a non-subcutaneous route.