OPINION published: 11 March 2021 doi: 10.3389/fimmu.2021.635371 Lack of Effectiveness of Repurposed Drugs for COVID-19 Treatment Miguel Angel Martinez* IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain Keywords: COVID-19, repurposed drugs, treatment efficacy, HIV, HCV INTRODUCTION 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. Edited by: Rashika El Ridi, Cairo University, Egypt FAILURE OF REPURPOSED DRUGS Reviewed by: Divakar Sharma, Repurposed drugs that have been explored more thoroughly since the beginning of the University of Delhi, India COVID-19 pandemic include remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferon, Ahmad Ali Othman, and hydroxychloroquine (1). Favipiravir, a purine nucleoside analog broad-spectrum inhibitor Tanta University, Egypt of viral RNA-dependent RNA polymerase (RdRp), approved for treatment of influenza virus *Correspondence: infection in Japan, was chosen due to its in vitro activity against SARS-CoV-2, nevertheless, Miguel Angel Martinez there is no evidence of its clinical efficacy. A prospective, randomized, open-label trial of early mmartinez@irsicaixa.es 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 Specialty section: investigated due to its SARS-CoV antiviral activity in tissue culture and infected patients. However, This article was submitted to the lopinavir-ritonavir combination exhibited no clinical benefit against SARS-CoV-2 (4). From Vaccines and Molecular Therapeutics, the very beginning of the COVID-19 pandemic, remdesivir has been the most promising drug a section of the journal against SARS-CoV-2. This adenosine nucleotide analog prodrug, a potentially inhibitor of RdRp, Frontiers in Immunology was initially developed by Gilead Sciences to treat filoviruses, such as the Ebola virus, and was Received: 01 December 2020 explored due to its broad-spectrum antiviral activity in tissue culture and animal models against Accepted: 19 February 2021 filoviruses, paramyxoviruses, pneumoviruses, and pathogenic coronaviruses, including SARS-CoV Published: 11 March 2021 and MERS-CoV. Randomized controlled trials (RCTs) have found no effect of remdesivir on Citation: mortality (5). This drug has been approved to treat COVID-19 in the USA and Europe, but Martinez MA (2021) Lack of Effectiveness of Repurposed Drugs for conclusive results to support the use of remdesivir are lacking (6, 7). COVID-19 Treatment. The use of aminoquinoline drugs chloroquine and hydroxychloroquine is paradigmatic of Front. Immunol. 12:635371. the failure of repurposed drugs to treat COVID-19. These cheap drugs are generic antimalarials doi: 10.3389/fimmu.2021.635371 used to treat amoebic liver abscess and rheumatic disease. The early promising results with Frontiers in Immunology | www.frontiersin.org 1 March 2021 | Volume 12 | Article 635371 Martinez Repurposed Drug Failure for COVID-19 these two drugs showing antiviral activity against SARS-CoV- Immunomodulators that appear to work are corticosteroids. 2 at micromolar concentrations in tissue culture and their A recent RTC performed with dexamethasone showed that, in clinical benefit in dubious observational trials of a few patients patients with moderate or severe COVID-19, dexamethasone positioned them at the forefront of possible treatments for plus standard care significantly increases survival and reduces COVID-19. However, large observational clinical trials and morbidity (14, 15). Other drugs that could offer clinical RCTs have shown no effect of hydroxychloroquine in reducing effects despite the lack of specific evidence for COVID- mortality and/or mobility (2). Moreover, in some studies, a worse 19 include anti-androgens, statins, N-acetyl cysteine, ACE2 infection course was observed in hospitalized patients treated inhibitors, angiotensin receptor blockers, and direct TMPRSS-2 with these aminoquinolines (8). Importantly, recent studies have inhibitors (16). demonstrated that chloroquine does not inhibit infection of Although immunomodulators may be an excellent clinical human lung cells with SARS-CoV-2 (9). Previous studies have tool, it is desirable to potently and specifically stop SARS-CoV- shown that chloroquine and hydroxychloroquine inhibit the 2 replication after the onset of the first COVID-19 symptoms ability of SARS-CoV-2 to infect African green monkey kidney- to avoid the pathogenic course of the disease. Ideally, we should derived Vero cells. However, when Vero cells were engineered to stop SARS-CoV-2 in the first days of the infection. For example, express TMPRSS2, a cellular protease that activates SARS-CoV- neuraminidase inhibitors may not produce any detectable effect 2 for entry into lung cells rendered SARS-CoV-2-infected Vero in a patient hospitalized with severe influenza virus infection, cells insensitive to chloroquine (9). Furthermore, chloroquine but can be useful in preventing the development of severe does not block infection with SARS-CoV-2 in TMPRSS2- disease. The most appropriate therapy goal of an acute viral expressing human lung Calu-3 cells, indicating that chloroquine infection is therefore not to cure severe disease, but to keep targets a pathway for viral activation that is not active in lung cells the disease from becoming severe, and prevent hospitalization. and is unlikely to protect against the spread of SARS-CoV-2. Treatment early in the course of illness could also limit person- These results emphasize the necessity of being cautious to-person transmission. with observed drug inhibition of viral replication in tissue A way to stop the early spread of SARS-CoV-2 will be through culture. Ivermectin, another cheap antiparasitic drug with in a sterilizing vaccine. SARS-CoV-2-neutralizing antibodies have vitro efficacy against SARS-CoV-2, is being prescribed as a been associated with protection (17). This is not surprising preventative against COVID-19. However, the evidence that as natural infection induces both mucosal antibody responses ivermectin protects people from COVID-19 is limited (10). We (secretory IgA) and systemic antibody responses (IgG). The should be prudent using ivermectin, or other potential drugs, upper respiratory tract is mostly protected by secretory IgA, outside clinical trials. In some countries, ivermectin is being whereas the lower respiratory tract is mostly protected by also administered to SARS-CoV-2 infected patients. Different IgG. Because most vaccines currently in development will be doses and posology have been used and confounding results administered intramuscularly or intradermally, they will induce have been reported. A recent pilot clinical trial found no mostly IgG, but no secretory IgA (18). Therefore, these vaccines significant differences in detection of SARS-CoV-2 RNA from would probably prevent disease but not generate sterilizing nasopharyngeal swabs at days four and seven after treating immunity; that is, they may still allow for transmission of the with a single oral dose of 400 mcrg/Kg of ivermectin (11). virus (18). In this scenario, the current pandemic will require Virus target specificity (e.g., isolation or drug-resistant viruses) different strategies utilized in concert, including an effective should be tested and demonstrated before initiating treatments in vaccine and competent antivirals. 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 HIV: A SUCCESS STORY to humans. HIV therapy is arguably among the most successful in treating any single human disease. The success of HIV therapeutics is illustrated by the number of antiretroviral agents and HIT EARLY, HIT HARD unique drug classes available (19). To date, the Food and Drug Administration (FDA) has approved 23 drugs to treat In addition to drugs specifically aimed to inhibit SARS-CoV-2 HIV infection. Based on their molecular mechanism and replication, therapeutics that modulate inflammation have also drug-resistance profile, antiretrovirals are classified into eight been tested and, in this case, they seem to be a more effective different classes: nucleoside reverse transcriptase inhibitors, non- therapeutic strategy for treating COVID-19 morbidity and nucleoside reverse transcriptase inhibitors, protease inhibitors, mortality. Immunomodulators are being tested in several clinical fusion inhibitors that block HIV entering CD4+ cells, CCR5 trials for the treatment of SARS-CoV-2-generated cytokine antagonists that block the CCR5 co-receptor that HIV needs storm. However, data to support the use of one of the most to enter the cells, integrase inhibitors, attachment inhibitors explored compounds to modulate inflammation, tocilizumab, that bind HIV glycoprotein 120, and post-attachment inhibitors a monoclonal antibody against interleukin-6 receptors, come that block cellular CD4 receptor. In addition to antiretrovirals, largely from observational studies (13). Large RCTs with one pharmacokinetic enhancer has been approved to increase tocilizumab should provide answers regarding its clinical benefit. antiretroviral effectiveness. In contrast to the diffuse viral targets Frontiers in Immunology | www.frontiersin.org 2 March 2021 | Volume 12 | Article 635371 Martinez Repurposed Drug Failure for COVID-19 of most of the repurposed drugs mentioned above, antiretroviral patients who have developed COVID-19, a rapidly progressive target specificity was defined through the in vitro or in vivo disease in whom might be more difficult to expect an antiviral selection of HIV-resistant variants for the different drugs. No to provide detectable benefit and more difficult to diagnose in antiretroviral has been approved in the absence of a specific its earlier stages when antiviral approaches would be more likely viral target. to be effective, HIV-1 and HCV examples should be mirrors in Although the virus was discovered in 1983, few antiretroviral which we should look for antiviral solutions. treatment options existed for HIV infection before 1996. HIV It can be argue that a repurposed drug that has not shown any therapeutics consisted mainly of prophylaxis against common benefit in hospitalized COVID-19 patients might still be useful in opportunistic pathogens and managing AIDS-related illnesses. slowing the development of illness, preventing severe disease and The development of HIV reverse transcriptase and protease making hospitalization unnecessary. In the absence of vaccines, inhibitors in the mid-1990s, and the introduction of drug a repurposed drug with limited antiviral activity might be given regimens that combined these two classes of inhibitors to increase to persons who have been exposed to an infected individual, or their efficacy, completely revolutionized the clinical approach to are in a situation in which exposure is likely to occur (post- HIV. These combination treatments transformed HIV infection or pre-exposure prophylaxis). However, such benefit would be from a life-threatening disease to a manageable chronic disease. more difficult to demonstrate than a standard RCT, but could The success of antiretroviral therapies has strongly impacted the still be tested. A combinatorial approach of repurposing drugs development of therapies against other viral infections. The best targeting both the virus and host target mechanisms has been also example is HCV, another pandemic, life-threatening, human viral proposed for the management of COVID-19 severity (21). The infection discovered in 1989. recent resolution of the crystal structures of the three most likely The first generation of FDA-approved HCV drugs included SARS-CoV-2 targetable proteins (spike, RdRp, and the main interferon alfacon-1 (approval year: 1997, discontinued in protease) is allowing the identification of first-generation SARS- 2013 due to severe adverse events), ribavirin (1998), pegylated CoV-2-specific antivirals (22–24). Even if the benefits of SARS- interferon alfa-2b (2001), and pegylated interferon alfa-2a (2002) CoV-2-specific antivirals remain to be elucidated, we should (20). Although these drugs had low cure rates, a treatment quickly move these first-generation specific and potent antivirals duration of 48 weeks, and may cause severe adverse events, to the clinic. they were the only standard-of-care treatments over a decade. Antiviral drugs approved for the treatment of human virus Interferons and ribavirin were chosen because they exhibited a infectious diseases have saved tens of millions of human beings certain inhibitory capacity against other viral infections, and their over the last decades. It is a challenge to pursue effective, low effectivity is largely due to their low specificity against HCV. low-toxicity, and well-tolerated drugs that enhance patient Fortunately, the development of direct-acting antivirals (DAAs) compliance and drug administration. Nevertheless, effective targeting the two main HCV enzymes, NS3 protease and RdRp antivirals will positively impact COVID-19 therapy, and SARS- (20), has decreased treatment duration to 8 weeks and increased CoV-2 transmission and eradication. the cure rate to nearly 100%. DAA therapy is among the best The success of antiretroviral and antiviral therapies developed examples of success in the fight against viral infections. DAAs against HIV and HCV should provide a point of reference have transformed HCV management and opened the door to the for SARS-CoV-2 drug development and a roadmap for the global eradication of HCV. development of novel COVOD-19 prevention strategies. DISCUSSION AUTHOR CONTRIBUTIONS Patients infected with HIV or HCV have a prolonged course of MM designed and wrote this manuscript. infection measured in months or years, during which they are asymptomatic or only mildly ill, providing ample opportunity to FUNDING intervene with an antiviral drug. 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Effect of dexamethasone on days alive and ventilator-free in patients and the copyright owner(s) are credited and that the original publication in with moderate or severe acute respiratory distress syndrome and COVID-19: this journal is cited, in accordance with accepted academic practice. No use, The CoDEX randomized clinical trial. J Am Med Assoc. (2020) 324:1307–16. distribution or reproduction is permitted which does not comply with these doi: 10.1001/jama.2020.17021 terms. Frontiers in Immunology | www.frontiersin.org 4 March 2021 | Volume 12 | Article 635371