Interferon-based therapies in COVID-19

The case-control study by Baghaei et al. [1] evaluated the effect of interferon-based combination therapy (interferon beta-1a in combination with lopinavir/ritonavir) in hospitalized patients with coronavirus disease 2019 (COVID-19). The authors aimed to compare the effect of the interferon-based combination therapy, which was administered to 152 case patients with COVID-19, with the control patients (n = 304) who received lopinavir/ritonavir alone, on all-cause mortality and other clinical outcomes. From the study, it was observed that the all-cause mortality rate in case and control groups was 11% and 13%, respectively, with no significant difference between the two groups.

The findings of Baghaei et al. [1] were consistent with the interim findings from the World Health Organization’s Solidarity Trial [2], which is an unprecedented global effort to evaluate four repurposed antiviral drugs including interferon beta-1a. The Solidarity Trial [2] reported no significant difference in the risk of death between patients with COVID-19 who received interferon beta-1a compared to its control (rate ratio = 1.16; 95% confidence interval 0.96–1.39; P = 0.11). While the results had been thus far disappointing for interferon beta-1a, we believe it may be premature to discard interferon-based therapies in our armamentarium against COVID-19. It is important to discuss possible reasons for better designing of future trials involving interferon-based therapies. Interferon-based therapies may only be effective for selected patients with COVID-19 and concurrent deficiencies in type I interferons, who harbored mutations in the genes related to the toll-like receptor 3 and interferon-I signaling pathways, or those who had autoantibodies that recognized type I interferons. To illustrate, Zhang et al. [3] who investigated if patients with a life-threatening course of COVID-19 had inborn errors of toll-like receptor 3 and interferon regulatory factor 7 dependent type I interferon immunity found that 3.5% of the individuals (n = 23/659) had mutations in 8 of these genes, rendering the gene products incapable of producing or responding to type I interferon. In contrast, among the 534 patients with either asymptomatic or mild course of COVID-19, only one harbored a loss-of-function in the concerned genes. On the other hand, Bastard et al. [4] reported that among the 987 people with a severe course of COVID-19 whom they included in their study, 135 (13.7%) had antibodies that recognized an interferon-α2, IFN-ω or both, whereas none of the 663 people with the asymptomatic or mild course of COVID-19 had the concerned autoantibodies.

The route of administration of interferon-based therapies may also play a factor: the bioavailability via the subcutaneous route is only approximately one-third of that via the intravenous route. The high serum concentration with the intravenous route of administration can optimize the distribution to the pulmonary vasculature, which would be difficult to achieve with the subcutaneous route of administration. Indeed, nebulized interferon-based therapy may even provide more targeted actions, and thus more favorable clinical responses. A randomized controlled trial [5] reported that patients with COVID-19 who received inhaled nebulized interferon beta-1a had greater odds of clinical improvement (odds ratio = 2.32; 95% confidence interval 1.07–5.04; p = 0.033) on day 15/16 compared to their counterparts who received placebo. In addition, the timing of treatment is critical where interferon-based therapy should preferably be administered in the early stage of the disease. Future trials involving interferon-based therapies could be performed in selected patients with COVID-19 and concurrent deficiencies in type I interferons who are more likely to benefit, with consideration of intravenous or inhalational route, and administration in the early course of the disease.