2. Antiviral agents
A large number of antiviral agents, many of which are used for the treatment of HIV, hepatitis and flu symptoms, are currently administered off-label worldwide in patients with COVID-19 or are under clinical evaluation for the treatment of the disease. Here we discuss the most used antivirals in terms of pharmacodynamic properties, potential for the treatment of COVID-19 and data from clinical studies where available. A brief analysis of antivirals less used is presented as well.
The combination lopinavir/ritonavir, which is indicated with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1), have raised increasing interest for the treatment of COVID-19. Lopinavir is a protease inhibitor with high specificity for HIV-1 and HIV-2, while ritonavir increases lopinavir plasma concentration through the inhibition of cytochrome P450 [10 ]. This combination was already tested in patients with SARS infection, demonstrating to be associated with favorable outcomes, and it is currently evaluated, in combination with interferon β, in patients with MERS-CoV infection [11-13 ]. Cao B et al. carried out a randomized, controlled, open-label trial in 199 hospitalized patients with severe SARS-CoV-2 infection. Patients were randomized to receive the combination lopinavir/ritonavir plus standard care for 14 days or standard care alone. According to study’s results, no differences between the combination treatment and the standard treatment, in terms of clinical improvement, mortality at 28 days and percentages of patients with detectable viral RNA, were detected. Moreover, adverse events, especially gastrointestinal ones, were more common in the group of patients receiving the combination treatment, while serious adverse events were more common in the standard-care group. Authors concluded that in hospitalized patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care [14 ]. Furthermore, an open-label, randomized clinical trial, which will compare the efficacy of lopinavir/ritonavir vs. hydroxychloroquine in 150 patients with mild COVID-19, is currently ongoing in the Republic of Korea [15 ]. Since clinical evidence on the efficacy and safety of the combination lopinavir/ritonavir in patients with COVID-19 is still limited and controversial, further studies are required to confirm a possible role of these drugs. Nevertheless, this combination is currently used in Italy in COVID-19 patients with less disease severity compared with patients evaluated in the study published on NEJM [14,16 ].
Remdesivir has been recently recognized as a promising antiviral drug against a broad-spectrum of RNA viruses (including MERS-CoV) infection in cultured cells [17 ], mice and non-human primate models [18 ]. It is a nucleotide analogue, able to inhibit RNA-dependent RNA polymerase (RdRp), proteins essential for viral replication. The drug was initially developed as a treatment for Ebola and Marburg infections, not demonstrating a clinical efficacy. Antiviral activities were also demonstrated against single-stranded RNA viruses, including MERS and SARS-Cov [19 ]. Recent results of a preclinical study indicated that, in vitro, the association remdesivir/chloroquine could be highly effective in controlling the SARS-Cov-2 infection [20 ]. The efficacy and safety of the remdesivir are currently evaluated in a phase 3 clinical trial in 453 patients with COVID-19 which will end in May 2020 [21 ]. In addition, a further phase 3 trial is evaluating the efficacy and safety of remdesivir in 1,000 patients with COVID-19; this study will end in May 2020 too [22 ]. Data from the Italian real clinical practice showed that the drug has already been used in patients with COVID-19 at the Spallanzani hospital in Rome, resulting in their full recovery [23 ]. Currently the drug is administered among 12 Italian clinical centers [24 ]. Lastly, a case report highlighted promising results of this treatment in the first US patient with COVID-19 [25 ].
Favipiravir is a further drug under clinical development. It was authorized in 2014 in Japan for the treatment of influenza virus infections. The drug is converted by intracellular phosphoribosylation into its active form that selectively inhibits RdRp. Since the catalytic domain of RdRp is expressed in many types of RNA viruses, favipiravir is effective against a wide range of influenza virus subtypes, but also against arenavirus, bunyavirus and filovirus [26 ]. Favipiravir has already been used for the treatment of patients with Ebola and Lassa viruses. However, no clear conclusions about the efficacy profile of the drug were drawn [27 ]. As reported by Watanabe et al. [28 ], favipiravir was administered during a clinical trial to 200 patients with COVID-19 at hospitals in Wuhan and Shenzhen. The results of these studies showed that patients who received the drug tested negative in a relatively short time (4 days compared to 11 days in the control group), while the symptoms of pneumonia significantly reduced. No specific safety concerns have emerged. Another clinical study carried out in Wuhan showed that favipiravir-treated patients recovered from fever after an average of 2.5 days, compared to 4.2 days of other patients. Chang Chen et al. [29 ] recently published the results of a randomized clinical trial (Chictr.org.cn, n. ChiCTR200030254), which compared the efficacy and safety of favipiravir vs. umifenovir in the treatment of 240 patients with COVID-19, hospitalized in 3 hospitals from 20 February 2020 to 12 March 2020. The results showed that the 7-day clinical recovery rate was 55.86% in the umifenovir group and 71.43% in the favipiravir group (P = 0.01). In patients with hypertension and/or diabetes, the time for fever reduction and cough relief was significantly shorter in favipiravir group than in umifenovir group (P<0.001), but no statistically significant difference regarding to oxygen therapy or non-invasive mechanical ventilation was found. The most common adverse events were liver enzyme abnormalities, psychiatric, gastrointestinal symptoms and serum uric acid elevations (2.5% of patients in the umifenovir group vs. 13.79% of patients in the favipiravir group, P <0.0001). Lastly, the drug is under evaluation for the treatment of COVID-19 in a 3-arms, multi-center randomized controlled trial in combination with tocilizumab [30 ]. At the end of March 2020 the Italian Medicine Agency (AIFA) started the evaluation of available scientific evidences with the aim to understand if a clinical program to assess the efficacy and safety of favipiravir is appropriate [31 ].
Further antiviral agents are considered as potential treatments in SARS-Cov-2 infection. For these antivirals a brief description is reported below. Among these, there is the combination darunavir/cobicistat, which is currently approved for the treatment of HIV-1 in association with other antivirals. Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease, while cobicistat is an inhibitor of cytochromes P450 that enhances darunavir plasma concentrations [32 ]. Based on the results of preclinical studies demonstrating inhibitory effects mediated by this combination on SARS-CoV-2 [33,34 ], this drug is currently evaluated in some clinical studies [35,36 ]. Lastly, an analysis carried out by Jeffrey K Aronson of clinical trials on COVID-19 revealed that there are currently more than 20 studies investigating the efficacy of further antivirals, including triazavirin (non-nucleoside antiviral drug effective against tick-borne encephalitis virus and forest-spring encephalitis virus), azidovudine (azidothymidine nucleoside analogue, inhibitor of HIV reverse transcriptase), umifenovir (membrane haemagglutinin fusion inhibitor in influenza viruses), danoprevir (Hepatitis C virus NS3 protease inhibitor) and baloxavir marboxil (inhibitor of influenza virus cap-dependent endonuclease) [37 ]. Sofosbuvir, galidesivir and tenofovir showed promising results for use against the newly emerged strain of coronavirus [38 ]. Other antivirals, such as oseltamivir, peramivir, zanamivir, ganciclovir, acyclovir, and ribavirin, which are commonly used in clinical practice, are currently not recommended for COVID-19 [8 ]. Even though few evidence have reported the use of some of these drugs in patients with COVID-19, researchers highlighted the importance to not give patients drugs of unknown efficacy, which might be very harmful for patients with severe COVID-19 [39 ].
Recently two other drugs are currently evaluated in patients with COVID-19, camostat mesilate and nafamostat. These drugs are synthetic protease inhibitors of trypsin, prostasin, matriptase and plasma kallikrein. They are approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. Coronaviruses penetrate the cell through the plasma membrane; this step requires the activation of superficial proteases, such as TMPRSS2. Specifically, SARS-CoV-2 enters human cells after that the S protein binds to an ACE2 receptor in the cell membrane. S protein is divided into S1 and S2 by a protease derived from human cells. S1 binds to its receptor, ACE2. The S2 is divided by TMPRSS2, with consequent fusion of the membrane. ACE2 and TMPRSS2 are therefore essential for SARS-CoV-2 infection. Both drugs are able to inhibit the enzymatic activity of TMPRSS2 [5,40 ]. A randomized, placebo-controlled clinical trial (CamoCO-19) is evaluating the efficacy and safety of camostat mesilate in 180 patients with COVID-19 [41 ]. Furthermore, both drugs will be evaluated in clinical trials launched by the University of Tokyo [42 ]. Camostat seems well tolerated; common adverse events include rashes, gastrointestinal disorders and changes in liver enzymes. Rare adverse events are thrombocytopenia, liver failure and hyperkalemia. Camostat mesilate was associated to a case of acute eosinophilic pneumonia [43 ]. Another glycoprotein involved in the passage of the virus inside the cell is CD147, which interacts with S protein. CD147 also shows pro-inflammatory activity and takes part in the regulation of cytokine secretion and in leukocytic chemotaxis during viral infections [44 ]. Chinese researchers have started a clinical trial to test the efficacy and safety of meplazumab, a monoclonal antibody that binds the CD147 glycoprotein. Even though this drug cannot be defined as an antiviral agent, its mechanism of action leads to a control in virus replication; for this reason, it is mentioned among antivirals. The preliminary results of the Chinese study are promising. Indeed, compared to the control group, the treatment with meplazumab was earlier associated with improvement in pneumonia. These results, although preliminary, seem to confirm the involvement of CD147 in the penetration and replication of the virus in the body as well as in the development of inflammatory processes related to the infection [45 ].
Lastly, a recent study carried out by the Monash University’s Biomedicine Discovery Institute and the Peter Doherty Institute of Infection and Immunity showed that ivermectin, a medication used for the treatment of parasite infestations, in cell culture is able to reduce the viral RNA of SARS-Cov-2 by 93% after 24 hours and by 99.8% after 48 hours. Currently, tests were carried out only in vitroand clinical trials are strongly need to evaluate if the drug can be really effective against SARS-Cov-2. The author concluded that the early administration of an effective anti-viral to patients could limit their viral load, contrast the disease progressing and prevent its transmission. They suggest that ivermectin could be a useful antiviral in the fight against Covid-19 [46 ].