Effect of Aprotinin and Avifavir® Combination Therapy for Moderate COVID-19 Patients

Abstract

COVID-19 is a contagious multisystem inflammatory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We studied the efficacy of Aprotinin (nonspecific serine proteases inhibitor) in combination with Avifavir® or Hydroxychloroquine (HCQ) drugs, which are recommended by the Russian Ministry of Health for the treatment therapy of moderate COVID-19 patients. This prospective single-center study included participants with moderate COVID-19-related pneumonia, laboratory-confirmed SARS-CoV-2, and admitted to the hospitals. Patients received combinations of intravenous (IV) Aprotinin (1,000,000 KIU daily, 3 days) and HCQ (cohort 1), inhalation (inh) treatment with Aprotinin (625 KIU four times per day, 5 days) and HCQ (cohort 2) or IV Aprotinin (1,000,000 KIU daily for 5 days) and Avifavir (cohort 3). In cohorts 1–3, the combination therapy showed 100% efficacy in preventing the transfer of patients (n = 30) to the intensive care unit (ICU). The effect of the combination therapy in cohort 3 was the most prominent, and the median time to SARS-CoV-2 elimination was 3.5 days (IQR 3.0–4.0), normalization of the CRP concentration was 3.5 days (IQR 3–5), of the D-dimer concentration was 5 days (IQR 4 to 5); body temperature was 1 day (IQR 1–3), improvement in clinical status or discharge from the hospital was 5 days (IQR 5–5), and improvement in lung lesions of patients on 14 day was 100%.

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…We contend that HTAs should also be considered ( 47 , 48 , 69 ), perhaps to bolster pairs of DAAs. The combination of a protease inhibitor (HTA, aprotinin, given IV) targeting the host enzyme TMPRSS2, plus oral favipiravir (DAA, polymerase inhibitor) has been tested in COVID-19 patients, but the study was too small to assess clinical efficacy ( 110 ). In murine models of infection, combinations of two anti-Spike MAbs plus RDV provided benefit over single agents in some measures of COVID-19 disease ( 111 ), supporting the concept of combined targeting of virus entry and viral polymerase activity.…”

Aprotinin treatment against SARS‐CoV‐2: A randomized phase III study to evaluate the safety and efficacy of a pan‐protease inhibitor for moderate COVID‐19

“…The nebulization method used in our study, which generates small particles (2–5 µm), can reach the bronchi and alveolae while avoiding dispersion and possible environmental contamination. 20 In a previous study, 26 a combination of intravenous and inhaled aprotinin with Avifavir ® (favipiravir) for patients with moderate COVID‐19 reduced viral load, ICU admission, and average hospitalization stay with improvement in lung lesions on the 14 th day of treatment. However, it was not clear whether these results were due to aprotinin or Avifavir ® or both.…”

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

“…The SARS-CoV-2 cytopathic effect and replication were alleviated by aprotinin in immortalized cells [ 106 ]. Combined therapy with aprotinin and favipiravir led to encouraging results in preventing progress of COVID-19 in patients requiring oxygen therapy [ 119 ]. Moreover, their hospital stays were diminished [ 119 ].…”

“…Combined therapy with aprotinin and favipiravir led to encouraging results in preventing progress of COVID-19 in patients requiring oxygen therapy [ 119 ]. Moreover, their hospital stays were diminished [ 119 ]. HGF activator inhibitors HAI-1 and HAI-2, transmembrane Kunitz-type protease inhibitors expressed in the prostate and the respiratory tract, and reduce TMPRSS2 activity in vitro by Ko et al [ 120 , 121 ].…”