Beneficial effect of combinational methylprednisolone and remdesivir in hamster model of SARS-CoV-2 infection

Abstract

Effective treatments for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Dexamethasone has been shown to confer survival benefits to certain groups of hospitalized patients, but whether glucocorticoids such as dexamethasone and methylprednisolone should be used together with antivirals to prevent a boost of SARS-CoV-2 replication remains to be determined. Here, we show the beneficial effect of methylprednisolone alone and in combination with remdesivir in the hamster model of SARS-CoV-2 infection. Treatment with methylprednisolone boosted RNA replication of SARS-CoV-2 in human monocyte-derived macrophages. Although methylprednisolone monotherapy alleviated body weight loss as well as nasal and pulmonary inflammation, viral loads increased and antibody response against the receptor-binding domain of spike protein attenuated. In contrast, a combination of methylprednisolone with remdesivir not only prevented body weight loss and inflammation, but also dampened viral protein expression and viral loads. In addition, the suppressive effect of methylprednisolone on antibody response was alleviated in the presence of remdesivir. Thus, combinational antiinflammatory and antiviral therapy might be an effective, safer and more versatile treatment option for COVID-19. These data support testing of the efficacy of a combination of methylprednisolone and remdesivir for the treatment of COVID-19 in randomized controlled clinical trials.

Broad-Spectrum Antiviral Activity of 3D8, a Nucleic Acid-Hydrolyzing Single-Chain Variable Fragment (scFv), Targeting SARS-CoV-2 and Multiple Coronaviruses In Vitro

“…Remdesivir conferred promising antiviral activity against SARS-CoV-2 in hACE2-transgenic mice [4,39] and rhesus macaques [40]. A combi-nation therapy of remdesivir with methylprednisolone showed beneficial effects against SARs-CoV-2 in hamsters [41]. A ribonucleoside analogue MK-4482/EIDD-2801 inhibited SARS-CoV-2 transmission in ferrets [42] and FDA-approved antivirals marginally reduced viral loads in SARS-CoV-2-infected ferrets [43].…”

The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance

“…Modeling of therapeutic confirmation, compared with disease modeling itself, is complicated by the interplay between host and therapeutic agent, remdesivir in this case. Nevertheless, there are several studies in the literature about efficacy of remdesivir against SARS-CoV-2 (Martinez et al 2021 ; Pruijssers et al 2020 ; Williamson et al 2020 ; Ye et al 2021 ; Yuan et al 2021 ). These studies are informative but the information is incomplete and/or inconsistent in terms of study design, dosage regimens, and/or the defined outcomes.…”

“…Ye et al investigated the efficacy of remdesivir in hamsters through intraperitoneal injection (Ye et al 2021 ). The treatment with remdesivir (15 mg/kg) was performed at 2 dpi and 3 dpi post-inoculation.…”

“…Remdesivir reduced the viral burden by ~ 20% in the lung tissue. It should be noted that viral titers were determined by plaque-forming assay in the Yuan study ( 2021 ), whereas the Ye study used RT-PCR assay (Ye et al 2021 ). The body weight of the remdesivir group was higher than that of the control group at 3 and 4 dpi (Yuan et al 2021 ).…”

“…The efficacy studies about remdesivir in animal models are informative but may not recapitulate clinical settings completely (Martinez et al 2021 ; Pruijssers et al 2020 ; Williamson et al 2020 ; Ye et al 2021 ; Yuan et al 2021 ). It is encouraging that all of the studies have demonstrated benefits from the use of remdesivir, however, such a conclusion cannot be convincingly drawn from human clinical studies (Beigel et al 2020 ; Goldman et al 2020 ; Grein et al 2020 ; Spinner et al 2020 ; Wang et al 2020 ).…”