Interferons in COVID-19: missed opportunities to prove efficacy in clinical phase III trials?

Interferons were repeatedly used in the therapy of COVID-19 due to their antiviral effects. Three recently published randomized controlled clinical phase III trials (WHO SOLIDARITY, ACTT-3, and SPRINTER) missed their primary objectives, i.e., a significant therapeutic effect of interferons was not demonstrated in these studies. In only one randomized controlled phase III trial (TOGETHER), a significant reduction in the hospitalization rate was revealed. Our study analyzes these findings, gives possible explanations for the failure of interferons, provides a proposal on how these agents could be successfully used, and also highlights the limitations of their employment in COVID-19. Interferons are apparently beneficial only if the patients are in the early stage of this disease and when they are usually not hospitalized, i.e., if the patients do not require oxygen support and/or if corticosteroids are not yet indicated. Furthermore, a higher dosage than the one used in the long-term treatment of multiple sclerosis with interferon beta or of chronic viral hepatitis with interferon alpha or lambda should be employed to achieve a better therapeutic effect in COVID-19.

Interferons in the Therapy of Severe Coronavirus Infections: A Critical Analysis and Recollection of a Forgotten Therapeutic Regimen with Interferon Beta.

The pharmacological and immunological properties of interferons, especially those of interferon beta, and the corresponding treatment strategies are described, and the results of studies with different interferons in coronavirus infections are analysed. Furthermore, the data obtained with high-dosed native interferon beta in life-threatening acute viral diseases as well as the results of clinical pilot studies with high-dosed recombinant interferon beta-1a are provided because they serve as the rationale for the proposed therapeutic regimen to be applied in acute viral infections. This regimen differs from those approved for treatment of multiple sclerosis and consists of interferon beta-1a administered as a 24 hour intravenous infusion at a daily dose of up to 90 µg for 3-5 consecutive days. Since under this regimen transient severe side effects can occur, it is analysed which patients are suitable for this kind of treatment in general and if patients with severe coronavirus infections could also be treated accordingly.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

BACKGROUND: Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising. METHODS: From 1992 to 2003, 59 patients (58 high-risk patients and 1 low-risk patient, median age 13 yrs; range, 8-25 yrs) were treated in the GPOH-NPC-91 study. The Stage II patient received irradiation as initial therapy. Fifty-eight patients received preradiation chemotherapy with methotrexate, cisplatin, and 5-fluorouracil. The cumulative radiation dose to primary sites was 59.4 Gy, a total dose of 45 Gy was delivered to the neck area. After irradiation, all patients were treated with 10(5) U recombinant IFN-beta/kg body weight 3 times a week for 6 months. RESULTS: After combination therapy, complete response was accomplished in 58 patients. In one patient, there was tumor progression during chemotherapy. In 3 patients, distant metastases were observed 14, 15, and 18 months after diagnosis, respectively. One patient had a local relapse 12 months after diagnosis. Fifty-four patients are still in first remission with a median follow-up of 48 months (range, 10-110 mos). Chemotherapy-related toxicity was mucositis Grade II, III, or IV in all patients and acute cardiotoxicity in 2 (3.5%) of the patients. Nephrotoxicity Grade I-II occurred in 8.8% of patients. CONCLUSIONS: The combination of initial chemotherapy, radiotherapy, and IFN-beta results in an excellent outcome. These results strongly support the development of a future treatment strategy along this line.