Data Suggest No Benefit of Anti-IL Drugs in Certain COVID Patients

NEW YORK (Reuters Health) – A new study provides no support for giving COVID-19 patients drugs that block the pro-inflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6), while another suggests the treatments could have drawbacks.

IL-1 and IL-6 blockade have been proposed as therapeutic strategies for COVID-19, but study results are mixed. To investigate further, the COV-AID trialists studied 342 adults (77% male, median age, 65 years) with COVID-19, hypoxic respiratory failure and signs of systemic cytokine release syndrome.

They were randomly assigned to IL-1 blockade (anakinra, n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (tocilizumab or siltuximab, n=227) or no IL-6 blockade (n=115).

“Despite a power approaching 90%, we could not detect a benefit for IL-1 or IL-6 pathway blockade on the time to clinical improvement when these drugs were given early in the disease course in a patient population with low to moderate 28-day mortality,” report Dr. Jozefien Declercq of University Hospital Ghent in Belgium and colleagues in The Lancet Respiratory Medicine.

The estimated median time to clinical improvement was 12 days with or without IL-1 blockade and 11 days with IL-6 blockade versus 12 days with no IL-6 blockade.

Even among patients on the high-end of the spectrum of measured cytokines at baseline (serum IL-1beta, IL-1 receptor antagonist and IL-6), there was no discernible an effect of IL-1 or IL-6 blockade, the researchers report.

Fifty-five patients died during the study, with no evidence for differences in mortality between treatment groups. The incidence of serious adverse events and serious infections was similar across treatment groups.

The researchers say “more research is needed to determine whether subgroups of patients might benefit or other biomarkers might identify responders more accurately. Although IL-6 blockade in combination with corticosteroids might be beneficial in the most severely ill patients, it seems less effective when used early in the disease course or in populations with low to moderate mortality,” they conclude.

The potential harms of IL-1 and IL-6 blockade also need to be considered, clinicians from Italy caution in a report in The Lancet Rheumatology.

They present evidence from a small observational study suggesting that IL-1 and IL-6 blocking therapies in use for the treatment of patients with severe COVID-19 can adversely affect the neutralizing activity of anti-SARS-CoV-2 antibodies.

Neutralizing activity of sera from patients treated with IL-1 or IL-6 inhibitors was significantly decreased compared with standard treatment, with 33% lower median neutralization activity in patients treated with IL-1 inhibitors and 39% lower median neutralization activity in patients treated with IL-6 inhibitors at day 30.

Similarly, at day 60, median neutralization activity was lower in patients treated with IL-1 inhibitors (32%) and IL-6 inhibitors (33%) compared with standard care, report Dr. Emanuel Della-Torre of Vita-Salute San Raffaele University, in Milan, and colleagues.

“These results raise three major and previously overlooked practical concerns about the long-term management of patients with COVID-19 treated with cytokine blocking strategies,” they write.

“First, as modeling has shown that the neutralizing activity of anti-SARS-CoV-2 antibodies predicts immune protection from symptomatic infection, the significant reductions in neutralizing activity observed in our study warrants careful reassessment of the risk of reinfection and of severe disease in patients treated with anti-IL-6 agents,” the researchers say.

“Second, while some national health-care programs advocate a single dose of vaccine in case of previous SARS-CoV-2 infection, our findings indicate that the effectiveness of one-jab programs should be carefully ascertained in patients recovered from COVID-19 who received IL-6 inhibitors as part of their anti-inflammatory therapy because this strategy could leave them with suboptimal protection,” they add.

“Accordingly, if these findings are confirmed in other cohorts, vaccination strategies should be carefully discussed in patients recovered from COVID-19 after treatment with IL-1 and IL-6 inhibitors and, possibly, implemented with regard to the optimal timing of vaccine administration,” they conclude.

SOURCE: https://bit.ly/3H4FsjM The Lancet Respiratory Medicine, online October 29, 2021 and https://bit.ly/3D45UYt The Lancet Rheumatology, online October 29, 2021.

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