In this study, we evaluated the efficacy of three antiviral regimes, namely, remdesivir (RDV), type 1 interferon β (IFNβ-1a or -1b), and RDV plus IFNs, in hospitalized MS patients admitted with COVID-19 on an electronic data set.
Our findings showed that RDV was associated with short hospitalization (less than one week), but this effect was observed only in patients who were not on anti-CD-20 agents. Taking IFNβ alone or in combination with RDV increased the hospitalization length by one week or more. However, this effect was seen specifically in patients who were already on anti-CD-20 agents. These findings suggest that the effectiveness of RDV in reducing hospitalization length may be influenced by the presence of anti-CD-20 agents, while the use of IFNβ in combination with anti-CD-20 agents may lead to longer hospital stays.
Rituximab or ocrelizumab is a monoclonal antibody that specifically targets the surface molecule CD20 [14] and is widely used to treat autoimmune diseases such as MS [15]. In our study, approximately half of MS patients admitted with COVID-19 were receiving rituximab at the time of hospital admission. Demonstrated studies show that rituximab effectively reduces inflammatory activity, the occurrence of relapses, and the formation of new brain lesions in patients with relapsing–remitting MS (RRMS) [9].
Rituximab specifically binds to CD20-positive B-lymphocytes, triggers cell-mediated apoptosis, and selectively depletes CD20 + B-cell activation [9, 16]. B cells serve various roles, such as differentiating into plasma cells to produce antibodies and facilitating the activation of T cells through antigen presentation [17], the production of soluble neurotoxic factors [18], and the switch to memory cells [19]. Memory B cells (MBCs) are essential for long-term immunity, as they generate new antibody-secreting cells with enhanced specificity upon encountering the same antigen again. However, rituximab treatment leads to complete depletion of B cells within 72 hours, and it takes approximately 6–9 months for B-cell recovery after the treatment is finished [20, 21]. Prolonged B-cell depletion hinders the adaptive immune response and the capacity to produce neutralizing antibodies, resulting in severe manifestations and a prolonged duration of COVID-19 infection [9, 22, 23]. In addition, the decreased immunoglobulin G levels in MS patients due to B-cell depletion [24] may result in persistent SARS-CoV-2 infection. Therefore, rituximab can reduce the host immune response, suppress viral replication, and increase the risk of prolonged viral shedding and infection [25].
It is important to consider the risks and benefits of rituximab treatment in patients with COVID-19, particularly those who are immunocompromised.
In the case of other clinical outcomes, our data did not demonstrate the benefit of prescribing RDV or IFNs in reducing the risk of in-hospital mortality or needing ICU admission. Of note, in our study population, therapies with IFNs and/or RDV were not related to 30-day survival.
During the pandemic, clinicians prescribe therapies for the treatment of COVID-19, which can limit the availability of medicines. Although there are no clinical trials specifically evaluating the efficacy and safety of RDV in patients with multiple sclerosis, it is the only antiviral agent that has received FDA approval for treating patients with mild to moderate COVID-19.
In trials conducted on the general population of COVID-19 patients, there is a lack of consensus on the clinical effectiveness of RDV. At present, the guidelines for the use of RDV against COVID-19 vary, leading to inconsistent recommendations, and the World Health Organization acknowledges the uncertainty surrounding its optimal role [9]. In a clinical trial conducted by Spinner et al.[26], the administration of RDV for 5 days in patients with COVID-19 pneumonia did not show any clinical benefit in moderate to severe cases of COVID-19. The results of the WHO Solidarity Trial Consortium, 2020, support the notion that RDV is not considered an essential drug for COVID-19-specific treatment[9], as suggested by the latest clinical guidelines (CDC, 2020; Ministry of Health and Labor, 2021; World Health Organization, 2021).
Our results showed that the administration of IFN-β alone or along with RDV was roughly one in three of our study population. Using IFN alone or in combination with RDV did not provide clinical benefits for MS patients in terms of reducing the mortality rate, reducing hospitalization, and reducing the need for ICU admission. These findings suggest that the use of IFN-β alone or in combination with RDV may not be effective for MS patients in terms of the outcomes mentioned.
According to observations in the course of virus infections such as SARS and MERS [27], the early use of interferon β, before starting a cytokine storm, appears to be safe and effective in treating COVID-19. Using IFN-β leads to alleviating symptoms, shortening viral shedding, and consequently reducing the need for respiratory support and duration of hospitalization through the acceleration of serum antibody onset against SARS-CoV-2.”
Multiple clinical trials have evaluated the efficacy and safety of interferon β-1a in treating severe COVID-19 [12, 28, 29]. A randomized controlled trial evaluating the efficacy of IFN-β1a in patients with severe COVID-19 showed a significantly lower 28-day mortality rate [12, 30]. Another study revealed that the combination of interferon β-1a with RDV did not show superiority over using RDV alone in hospitalized patients with COVID-19 pneumonia [28]. The WHO Solidarity Trial did not show any additional advantages of using interferons in conjunction with supportive care [13]. A more recent study also did not find any additional advantages of using interferon β-1a in combination with RDV [23]. Both studies were constrained by delayed treatment initiation after symptom onset and the absence of a viral load profile. It is important to note that while interferon β has shown promise in treating COVID-19, its effectiveness in treating other diseases, such as MS, may differ. A review of the literature on interferon β in MS found that it has wide immunomodulatory effects, resulting in its efficacy in treating MS [12, 31]. However, it is unclear whether interferon β alone or in combination with other drugs is effective in treating MS patients with COVID-19.
Based on our findings, RVD and/or IFN therapy was administered more frequently in patients with affected lung(s) or in patients with O2 saturation less than 93% at the time of admission compared to those with mild COVID-19. Our data showed that taking antiviral agents had a significant association with needing oxygen therapy during hospitalization. It seems that ordering IFNs, RDV, or IFNs plus RDV is more common in patients with severe disease. To address their efficacy, the severity of the disease was adjusted in multivariable regression models.
It is worth noting that the efficacy of antiviral therapy may be associated with the number of days after symptom onset, but we did not have access to these data. However, the variability of the time interval between symptom onset and treatment initiation, which is a crucial factor for evaluating antiviral drugs, remains a limitation. Regarding the need for oxygen supplements, we did not have access to the start date of oxygen therapy or invasive oxygen therapy in our data.