Background: Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19.
Methods: This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Findings: Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3-7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5-11]) than the control group (12 days [8-15]; hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir-ritonavir because of biochemical hepatitis. No patients died during the study.
Interpretation: Early triple antiviral therapy was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.
Methods: We analyzed a large sample of 2,757 genotyped and imputed patients from two cohorts, split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.
Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1×10-26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6×10-19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR=2.88 (2.29-3.61), p=7.4×10-20) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7×10-09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR=7.35 (4.33-12.47), p=1.5×10-13). These haplotypes exhibit large population-specific frequency differences. In a cohort of IFNβ-1a s.c.-treated patients, prediction models for nADA reached an AUC of 0.91 (0.85-0.95), a sensitivity of 0.78, and a specificity of 0.90. Patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR of 73.9 (11.8 463.6, p=4.4×10-06) of developing nADA.
Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.
Background: Coronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.
Methods: We performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.
Results: A unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFκB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.
Conclusion: We propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.
Objectives: To the best of our knowledge, there is no published study regarding use of IFN beta-1a in the treatment of severe COVID-19. In this randomized clinical trial efficacy and safety of IFN β-1a has been evaluated in patients with severe COVID-19.
Methods: Forty-two patients in the interferon group received IFN beta-1a in addition to the standard of care. Each 44 micrograms/ml (12 million IU/ml) of interferon beta-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group received only the standard of care. Primary outcome of study was time to reach clinical response. Secondary outcomes duration of hospital stay, length of ICU stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects and complications during the hospitalization.
Results: As primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 +/- 5.8 vs. 8.3 +/- 4.9 days respectively, P=0.95). On day 14, 66.7% vs. 43.6% of patients in the IFN group and the control group were discharged, respectively (OR= 2.5; 95% CI: 1.05- 6.37). The 28-day overall mortality was significantly lower in the IFN then the control group (19% vs. 43.6% respectively, p= 0.015). Early administration significantly reduced mortality (OR=13.5; 95% CI: 1.5-118).
Conclusion: Although did not change time to reach the clinical response, adding to the standard of care significantly increased discharge rate on day 14 and decreased 28-day mortality.
Background: COVID-19 pneumonia is associated with significant mortality and has no approved antiviral therapy. Interferon beta1 has shown in vitro studies a potent inhibition of SARS-CoV and MERS-CoV. In an in vitro study, SARS-CoV-2 had more sensitivity to IFN-I pretreatment that SARS-CoV. A combination of IFN beta1b administered subcutaneously with other antiviral treatments has been recommended in several guidelines. However, clinical trial results for the treatment of COVID-19 are pending. We aimed to assess the efficiency of IFN beta1b in COVID19 comparing the in-hospital mortality between patients who received IFN beta1b and patients did not receive.
Methods: In this retrospective cohort study, we included hospitalized adults with COVID-19 between February 23th and April 4th, 2020, at the Central Defense Hospital (Madrid, Spain). Subcutaneous interferon beta-1b was recommended in moderate-severe pneumonia. The primary endpoint was in-hospital mortality. Univariate and multivariate analysis was performed to identify variables associated with in-hospital mortality.
Findings: We analyzed 256 patients (106 patients in interferon group and 150 patients in control group). At admission, patients who did not receive interferon beta1b presented a greater number of comorbidities. The overall mortality rate was 24.6% (63/256). Twenty-two patients (20.8%) in the interferon group died and 41 (27.3%) in the control group (p=0.229). In the multivariate analysis, the predictors of in-hospital mortality were age, severity of clinical picture at admission and hydroxychloroquine treatment.
Interpretation: In hospitalized patients with COVID-19, interferon beta1b treatment was not associated to decrease in-hospital mortality. Further assessment of the earlier administration of this drug in randomized trials is recommended.