Lack of Effectiveness of Repurposed Drugs for COVID-19 Treatment

Abstract

The magnitude of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the repurposing of several drugs to quickly stop the morbidity, mortality, and spread of this new disease. Repurposed drugs tested to fight COVID-19 have been chosen mainly on the basis of promising in vitro efficacy against SARS-CoV-2 or on previous therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (1). Numerous clinical trials have already been completed, but no repurposed drug evaluated to date has been found that could significantly impact the course of COVID-19 pandemic (2). Our experience with previous viral pandemics, such as human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV), has taught us that precise design and target specificity will be essential to obtaining potent and successful antivirals against SARS-CoV-2. Repurposed drugs that have been explored more thoroughly since the beginning of the COVID-19 pandemic include remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferon, and hydroxychloroquine (1). Favipiravir, a purine nucleoside analog broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp), approved for treatment of influenza virus infection in Japan, was chosen due to its in vitro activity against SARS-CoV-2, nevertheless, there is no evidence of its clinical efficacy. A prospective, randomized, open-label trial of early vs. late favipiravir in hospitalized patients with COVID-19 has shown that favipiravir did not significantly improve viral clearance (3). Lopinavir-ritonavir, a HIV-1 protease inhibitor, was investigated due to its SARS-CoV antiviral activity in tissue culture and infected patients. However, the lopinavir-ritonavir combination exhibited no clinical benefit against SARS-CoV-2 (4). From the very beginning of the COVID-19 pandemic, remdesivir has been the most promising drug against SARS-CoV-2. This adenosine nucleotide analog prodrug, a potentially inhibitor of RdRp, was initially developed by Gilead Sciences to treat filoviruses, such as the Ebola virus, and was explored due to its broad-spectrum antiviral activity in tissue culture and animal models against filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses, including SARS-CoV and MERS-CoV. Randomized controlled trials (RCTs) have found no effect of remdesivir on mortality (5). This drug has been approved to treat COVID-19 in the USA and Europe, but conclusive results to support the use of remdesivir are lacking (6, 7). The use of aminoquinoline drugs chloroquine and hydroxychloroquine is paradigmatic of the failure of repurposed drugs to treat COVID-19. These cheap drugs are generic antimalarials used to treat amoebic liver abscess and rheumatic disease. The early promising results with these two drugs showing antiviral activity against SARS-CoV-2 at micromolar concentrations in tissue culture and their clinical benefit in dubious observational trials of a few patients positioned them at the forefront of possible treatments for COVID-19. However, large observational clinical trials and RCTs have shown no effect of hydroxychloroquine in reducing mortality and/or mobility (2). Moreover, in some studies, a worse infection course was observed in hospitalized patients treated with these aminoquinolines (8). Importantly, recent studies have demonstrated that chloroquine does not inhibit infection of human lung cells with SARS-CoV-2 (9). Previous studies have shown that chloroquine and hydroxychloroquine inhibit the ability of SARS-CoV-2 to infect African green monkey kidney-derived Vero cells. However, when Vero cells were engineered to express TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells rendered SARS-CoV-2-infected Vero cells insensitive to chloroquine (9). Furthermore, chloroquine does not block infection with SARS-CoV-2 in TMPRSS2-expressing human lung Calu-3 cells, indicating that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2. These results emphasize the necessity of being cautious with observed drug inhibition of viral replication in tissue culture. Ivermectin, another cheap antiparasitic drug with in vitro efficacy against SARS-CoV-2, is being prescribed as a preventative against COVID-19. However, the evidence that ivermectin protects people from COVID-19 is limited (10). We should be prudent using ivermectin, or other potential drugs, outside clinical trials. In some countries, ivermectin is being also administered to SARS-CoV-2 infected patients. Different doses and posology have been used and confounding results have been reported. A recent pilot clinical trial found no significant differences in detection of SARS-CoV-2 RNA from nasopharyngeal swabs at days four and seven after treating with a single oral dose of 400 mcrg/Kg of ivermectin (11). Virus target specificity (e.g., isolation or drug-resistant viruses) should be tested and demonstrated before initiating treatments in virus-infected patients. As hydroxychloroquine showed no effect in SARS-CoV-2 infection in non-human primates (12), testing animal models will be preferable before translating these drugs to humans. In addition to drugs specifically aimed to inhibit SARS-CoV-2 replication, therapeutics that modulate inflammation have also been tested and, in this case, they seem to be a more effective therapeutic strategy for treating COVID-19 morbidity and mortality. Immunomodulators are being tested in several clinical trials for the treatment of SARS-CoV-2-generated cytokine storm. However, data to support the use of one of the most explored compounds to modulate inflammation, tocilizumab, a monoclonal antibody against interleukin-6 receptors, come largely from...