DISCUSSION
nausea, SARS-CoV-2 infection, diarrhea
DISEASE PROGRESSION, SARS-COV-2 INFECTION, ADVERSE EVENTS, SECONDARY, ADVERSE EVENT
In this exploratory, randomized, controlled clinical trial, compared with standard-of-care alone, nelfinavir combined with standard-of-care treatment did not significantly reduce the time to clearance of SARS-CoV-2. Analyses of the secondary endpoints, viral load, and COVID-19-related symptoms indicated similar results. These results do not support the use of nelfinavir for the treatment of patients infected with SARS-CoV-2 having no or mild COVID-19 symptoms.In this study, the dosage of nelfinavir (750 mg; thrice daily) was based on the following reports. First, a mathematical model simulating the treatment of SARS-CoV-2 infection with nelfinavir suggested that a dosage of 500 mg twice daily was sufficient to reduce viral load (However, it is unclear whether the dosage is adequate to suppress viral replication in the respiratory epithelial cells and lung tissues of patients with COVID-19. Although the results of a previous study showed that after oral administration, the average concentration of nelfinavir was 3.24 times higher in the lung than in the plasma of rats (Another possible explanation for the lack of potent activity is the emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2. When Ohashi et al. reported that nelfinavir inhibited the catalytic activity of the SARS-CoV-2 main protease in a dose-dependent manner (The The most frequent adverse events in patients receiving nelfinavir were diarrhea and nausea. These adverse events were also reported in the clinical trials of patients infected with HIV, wherein diarrhea was the most frequently reported adverse event (Some limitations of the present study should be mentioned. First, the sample size was not sufficiently large to assess the time to disease progression. Therefore, this outcome was not incorporated into the present exploratory study. Although preventing disease progression is the primary objective of treating patients infected with SARS-CoV-2, a large-scale, randomized, controlled trial is needed to assess the effect of nelfinavir treatment on this outcome. Second, the concentration of nelfinavir in the lung was not measured. Third, bias in assessing the symptoms of patients could not be minimized, as an open-label scheme was used.In conclusion, nelfinavir combined with standard-of-care was not associated with a reduction in the time to viral clearance in patients infected with SARS-CoV-2 who had no or mild symptoms. During the course of this clinical trial, the findings of three experimental studies of nelfinavir treatment using the Syrian hamster model of SARS-CoV-2 infection were reported. First, Jan et al. showed that nelfinavir reduced the viral titer in the lung of SARS-CoV-2-infected Syrian hamsters (