Low mortality rate observed in a small case series published in Critical Care suggests that combination treatment of favipiravir and nafamostat mesylate may be effective for critically ill coronavirus disease 2019 (COVID-19) patients.
“Nafamostat mesylate therapy in combination with favipiravir may allow blockade of virus entry and replication, as well as inhibition of pathogenic host response, i.e., hyper-coagulopathy,” Kent Doi, Department of Acute Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, and colleagues concluded.
The authors noted that nafamostat mesylate was shown to inhibit the entry of SARS-CoV-2 into the human epithelial cells at EC50 of ~ 10 nM in previous studies, while favipiravir is expected to have antiviral action against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as it exhibits antiviral activity against other RNA viruses.
The study included 11 RT PCR-confirmed SARS-CoV-2-infected adults who were admitted to the intensive care unit (ICU) at The University of Tokyo Hospital between April 6 and April 21, 2020, and treated with the combination of nafamostat mesylate and favipiravir. The majority of these patients (91%) were males with the median age of 68 years (interquartile range [IQR] 60–69). The most common comorbidity among the patients was hypertension (36%) and diabetes melitus (27%).
The median PaO2/FiO2 ratio of these patients were 131 (IQR 114–198). All patients required oxygen therapy, where 8 (73%) of them were placed on invasive mechanical ventilation (MV), and 3 (27%) needed venovenous extracorporeal membrane oxygenation (VV-ECMO).
In the study, patients received combination treatment of nafamostat mesylate at 0.2 mg per kg per hour by continuous intravenous infusion (median treatment 14 days [IQR, 10 to 14 days]) and favipiravir at 3600 mg on day 1 and at 1600 mg per day on day 2 onwards (median treatment 14 days [IQR, 12 to 14 days]). The authors reported that no interruption of antiviral treatment occurred due to adverse drug reactions except for one patient who developed hyperkalemia on day 9 (by nafamostat mesylate).
The authors noted that all 11 patients had a minimum of 33 days of hospital follow-up. As of May 22, 1 patient, who had a do-not-resuscitate order, died on ICU day 7. Meanwhile, 7 patients were successfully weaned from MV (median duration of MV 16 days [IQR, 10-19]); 7 patients were discharged from the hospital while 2 were transferred to general ward and 1 remained in ICU without MV.
“This is the first report on nafamostat mesylate treatment in combination with favipiravir against COVID-19,” the authors wrote, adding that this case series demonstrated a low mortality rate (9%) despite a high number of patients (73%) who required MV, in comparison with previous reports on critically ill patients with COVID-19. “Although the number of patients in this case series was very small, this low mortality rate suggests that combination treatment of favipiravir and nafamostat mesylate may be effective for critically ill COVID-19 patients,” they concluded.
The authors added that patients with severe COVID-19 often suffer from microvascular thrombosis and hemorrhage with extensive alveolar and interstitial inflammation in the lung. Thus, nafamostat mesylate “might be an effective treatment” because “it inhibits intravascular coagulopathy, in addition to directly targeting the virus entry in host epithelial cells”. They also said that a clinical trial using the combination of nafamostat mesylate and favipiravir to treat COVID-19 will be initiated in Japan.