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 ].