2. Clinical evidence of antiviral agents
A large number of antiviral agents, many of which are used for the
treatment of other diseases, are currently undervaluation for COVID-19.
The figure 2 shows the main drugs evaluated for COVID-19 and their
mechanisms of action. We reported below those for which clinical
evidence on their safety and efficacy is available.
Remdesivir is an antiviral drug effective against a broad
spectrum of RNA viruses (including MERS-CoV and and SARS-CoV) (Agostini
et al., 2018; de Wit et al., 2020; Sheahan et al., 2020). It is a
nucleotide analogue that inhibits the RNA-dependent RNA polymerase
(RdRp) essential for viral replication. A randomised, double-blind,
placebo-controlled, multicenter trial, conducted on adults (aged ≥18
years) admitted to hospital with laboratory-confirmed SARS-CoV-2
infection, showed no difference for the time to clinical improvement
between the remdesivir group and the placebo group (Wang et al., 2020b).
A randomized, open-label trial, evaluating the efficacy of 5 or 10 days
of remdesivir treatment compared to the standard care in hospitalized
patients with confirmed severe acute respiratory syndrome and moderate
COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation
>94%), showed that patients treated with 10-day course of
remdesivir had no statistically significant difference in clinical
status (at 11 days) compared to standard care. On the contrary, those
treated with 5-day course of remdesivir had a statistically significant
difference in clinical status, but the difference was defined as
uncertain for clinical importance (Spinner et al., 2020). A
double-blind, randomized, placebo-controlled trial (NIAID-ACTT-1) of
intravenous remdesivir administered to adults hospitalized for COVID-19
showed that remdesivir was superior to placebo in shortening the time to
recovery. Specifically, patients receiving remdesivir had a median
recovery time of 10 days (95% confidence interval [CI], 9 to 11)
compared with 15 days of patients receiving placebo (95% CI, 13 to 18)
(Beigel et al., 2020). Finally, a randomized, open-label, phase 3 trial
on hospitalized patients with severe COVID-19 not requiring mechanical
ventilation, which were randomized to receive intravenous remdesivir for
5 or 10 days, showed no difference in terms of clinical status between
the two groups (Goldman et al., 2020). A meta-analysis of aforementioned
clinical trials showed that the treatment with remdesivir for 10 days
increased the recovery rate at day 14 in severe COVID-19 patients
(RR=1.5, 95%CI 1.33-1.7) and at day 28 in moderate and severe COVID-19
patients (RR=1.14, 95%CI 1.06-1.22). Additionally, in all patients,
remdesivir decreased the mortality rate at day 14, but not at day 28.
The best response to remdesivir for both recovery and mortality rates
was observed in nonmechanically ventilated COVID‐19 patients at day 14
(Elsawah et al., 2020).
Among observational data, a study conducted on patients under mechanical
ventilation with confirmed COVID-19 showed a significant beneficial
effect of remdesivir on survival (Pasquini et al., 2020). Moreover, a
clinical improvement was also observed in hospitalized patients with
severe COVID-19 who were treated with compassionate-use remdesivir
(Grein et al., 2020).
Based on the results of the NIAID-ACTT-1 trial, the European Medicine
Agency (EMA) has granted a conditional marketing authorisation to
remdesivir (Veklury©) for the treatment of adults and
adolescents from 12 years of age with COVID-19 pneumonia who require
supplemental oxygen. Remdesivir is the first medicine that was
recommended for COVID-19 in Europe with data evaluated in a short
timeframe through a rolling review procedure, which is an approach used
during public health emergencies to rapidly evaluate data. However, on
November 20th, 2020 the World Health Organization
(WHO) has issued a conditional recommendation against the use of
remdesivir in hospitalized patients with COVID-19, regardless of disease
severity, as there is no evidence demonstrating an improvement of
survival or other outcomes during its use in these patients. This
recommendation is based on the interim results of the open-label WHO
Solidarity Trial and from data of 3 other randomized controlled trials,
considering data from over 7000 patients across the 4 trials (World
Health Organization). Currently, the Committee for Medicinal Products
for Human Use (CHMP) of EMA is evaluating data on mortality at day 28
derived from the NIAID-ACTT-1 trial. Moreover, the EMA has requested the
full Solidarity data from WHO and the marketing authorisation holder in
order to assess, together with any other relevant available data, if any
changes are needed to the marketing authorisation of remdesivir. In
terms of safety, the EMA is also evaluating a signal for kidney
toxicity, a condition that could have other causes in COVID-19 patients
(European Medicine Agency).Lopinavir/ritonavir is a combination composed by lopinavir, a
protease inhibitor with high specificity for HIV-1 and HIV-2, and
ritonavir, an inhibitor of cytochrome P450 that allows to increase
lopinavir plasma concentration (Scavone et al., 2020). First results
from a randomized trials conducted in patients with SARS-CoV-2 infection
did not show any benefit for this combination compared to the standard
care alone (Cao et al., 2020; Li et al., 2020d), even though the triple
antiviral therapy (lopinavir/ritonavir, ribavirin, and interferon
beta-1b) was safer and more effective than lopinavir/ritonavir alone
(Hung et al., 2020).In addition, the RECOVERY trial that aimed to
compare a range of possible treatments with usual care in patients
hospitalized for COVID-19 showed no reductions in 28-day mortality,
duration of hospital stay, or risk of progressing to invasive mechanical
ventilation or death for the lopinavir/ritonavir group (Horby et al.,
2020b). A recent meta-analysis, comparing the treatment with
lopinavir/ritonavir with the standard of care/control or any other
antiviral agent/combinations, showed no difference between the
lopinavir/ritonavir combination and the standard of care in terms of
progression to more severe state, mortality, and virological cure on
days 7-10. Moreover, no difference in efficacy was observed with
lopinavir/ritonavir compared to umifenovir or hydroxychloroquine
(Bhattacharyya et al., 2020). Another meta-analysis demonstrated no
significant difference in terms of negative polymerase chain reaction
(PCR) results between patients treated with lopinavir/ritonavir and
those treated with the standard care (Wang et al., 2020a). Data from
observational studies revealed no differences between
lopinavir/ritonavir and hydroxychloroquine administered in patients with
severe or mild-moderate COVID-19 (Choi et al., 2020; Karolyi et al.,
2020; Lecronier et al., 2020). A retrospective study, conducted instead
in non-severe patients with COVID-19, also showed no improvement in the
prognosis or shortening of clinical course with lopinavir/ritonavir
treatment (Gao et al., 2020). On the contrary, a retrospective cohort
study showed that the combined antiviral therapy (lopinavir/ritonavir
plus umifenovir) is more effective than lopinavir/ritonavir monotherapy
(Deng et al., 2020). Based on the available evidence, the regular use of
lopinavir/ritonavir in the treatment of COVID-19 cannot be supported.
Some evidences suggest its use as a combination therapy but further
clinical trials are needed to evaluate lopinavir/ritonavir’s efficacy
and safety in COVID-19 patients.
Favipiravir is a drug authorized for the treatment of influenza
virus infections in Japan. It is a prodrug converted by intracellular
phosphoribosylation into the active form able to inhibit the RdRp.
Preliminary data suggested its safety and efficacy in shortening the
time to recovery and in reducing pneumonia symptoms (Scavone et al.,
2020; WATANABE et al., 2020). A randomized clinical trial, comparing the
efficacy and safety of favipiravir vs umifenovir in hospitalized
patients with COVID-19, demonstrated a higher efficacy for favipiravir
than umifenovir (p= 0.01). Regarding adverse events, liver enzyme
abnormalities, psychiatric disorders, gastrointestinal symptoms, and
serum uric acid elevations were those most commonly reported (Chen et
al., 2020a). An open-label study, evaluating the effects of favipiravir
versus lopinavir/ritonavir in patients with COVID-19 who were also
treated with aerosol inhalation of interferon (IFN)-α, showed a faster
viral clearance and a better chest computed tomography change for the
favipiravir group. Additionally, fewer adverse events were observed in
the favipiravir group than lopinavir/ritonavir group (Cai et al., 2020).
On the contrary, the combination favipiravir and inhaled IFN beta-1b
showed no difference for inflammatory biomarkers at hospital discharge
and for the overall length of hospital stay when compared to
hydroxychloroquine(Khamis et al., 2020). Another study, aiming to
evaluate the clinical outcomes and plasma concentrations of baloxavir
marboxil and favipiravir in COVID-19 patients, failed in demonstrating a
virological effect and clinical benefits of these two drugs. Authors
concluded that this result could be determined by the insufficient
concentrations of these drugs relative to their antiviral activities
(Lou et al., 2020). An adaptive, multicenter, open label, randomized,
phase II/III clinical trial of favipiravir versus standard of care in
hospitalized patients with moderate COVID-19 pneumonia demonstrated a
rapid antiviral response with favipiravir (Ivashchenko et al., 2020).
Based on these preliminary results, the Russian Ministry of Health
granted, in May 2020, a fast-track marketing authorization to
favipiravir for the treatment of COVID-19 patients. A meta-analysis of
some aforementioned clinical trials showed a significant clinical and
radiological improvement with favipiravir compared to the standard of
care, but no significant difference with regards to viral clearance,
oxygen support requirement, or side effects (Shrestha et al., 2020).
Currently, two clinical trials are ongoing to evaluate the efficacy and
safety of favipiravir alone (NCT04336904) or in combination with
tocilizumab (NCT04310228) for the treatment of COVID-19.
The promising effectiveness of favipiravir for COVID−19 was also showed
in a retrospective observational study (Rattanaumpawan et al., 2020).
Based on the available evidence, favipiravir is effective in alleviate
symptoms and in the clinical improvement of COVID-19 patients but
further studies are need to prove its benefit in terms of viral
clearance, oxygen support requirement, and mortality.Darunavir/cobicistat is another agent considered as a potential
treatment for SARS-CoV-2 infection. Darunavir is an inhibitor of
dimerization and of the HIV-1 protease, while cobicistat is an inhibitor
of cytochromes P450 that increases darunavir plasma concentration
(Deeks, 2018). Today, there are conflicting in vitro data on the effect
of darunavir in inhibiting SARS-CoV-2 viral replication (Alshaeri and
Natto, 2020; De Meyer et al., 2020). Results from a single-center,
randomized, and open-label trial of darunavir/cobicistat plus interferon
alpha 2b vs interferon alpha 2b alone in COVID-19 patients showed no
difference in the proportion of negative PCR results at day 7 between
the two groups (Chen et al., 2020b). Nicolini et al reported the results
on the real-life use of darunavir/cobicistat in severe COVID-19
patients. Their findings showed that, although well tolerated, this
treatment did not reduce mortality in COVID-19 (Nicolini et al., 2020).
On the contrary, a case-control study showed a lower mortality for
darunavir/cobicistat group than the control group (Odds Ratio, OR 0.07,
95%CI 0.01-0.52, p=0.009) in critically ill patients with SARS-CoV-2
infection (Kim et al., 2020).Triazavirin , a guanosine nucleotide analogue that inhibits RNA
synthesis, was compared to placebo in a pilot randomized controlled
trial for the treatment of COVID-19. This study found no difference in
the time to clinical improvement between groups in spite of a less
frequent use of concomitant therapies for respiratory, cardiac, renal,
hepatic, or coagulation supports in the triazavirin group (Wu et al.,
2020). Currently, a randomized, phase 2/3 clinical trial is evaluating
the effects of triazavirin vs. placebo in inpatients with mild-moderate
COVID-19 (the study will end at December 31, 2021) (NCT04581915).Umifenovir is a membrane hemagglutinin fusion inhibitor that
blocks the attachment of viral envelope protein to host cells (Liu et
al., 2020a). As mentioned above, some clinical trials failed to prove a
clinical benefit with umifenovir compared to supportive care (Li et al.,
2020d) or favipiravir (Chen et al., 2020a) in COVID-19 patients.
However, an observational study suggested its superiority to
lopinavir/ritonavir in shortening the duration of positive RNA in
COVID-19 patients (Zhu et al., 2020). Clinical trials are ongoing to
evaluate the efficacy and safety of umifenovir (NCT04260594) or
umifenovir, oseltamivir, and lopinavir/ritonavir (NCT04255017) for the
treatment of COVID-19.Danoprevir is a hepatitis C virus NS3 protease inhibitor that
was firstly evaluated compared to lopinavir/ritonavir in COVID-19
patients. The study found that the group treated with danoprevir had a
shorter mean time to achieve both negative nucleic acid testing and
hospital stays than lopinavir/ritonavir group (Zhang et al., 2020c). Two
clinical trials are ongoing to evaluate the efficacy and safety of
danoprevir in combination with ritonavir (NCT04345276) or ritonavir plus
interferon (NCT04291729).Sofosbuvir and daclatasvir are direct-acting
antivirals that represent potential candidates for the treatment of
COVID-19. A trial, evaluating the effectiveness of sofosbuvir and
daclatasvir compared to ribavirin in patients with severe COVID-19,
showed a relative risk of death of 0.17 (95% CI 0.04-0.73, P = 0.02)
for the sofosbuvir/daclatasvir group (Eslami et al., 2020). Similarly,
an open-label, multicentre, randomized controlled clinical trial
conducted in adults with moderate or severe COVID-19 showed that the
group treated with sofosbuvir/daclatasvir plus standard care had a
significant reduction of the duration of hospital stay compared with
standard care alone (Sadeghi et al., 2020). A single-centre, randomized,
controlled trial of adults with moderate COVID-19, comparing the
treatment with sofosbuvir, daclatasvir, and ribavirin to the standard
care, demonstrated instead no difference in terms of median duration of
hospital stay, number of Intensive care Unit (ICU) admissions, and the
number of deaths between groups, but the cumulative incidence of
recovery was higher in the sofosbuvir/daclatasvir/ribavirin group
(Abbaspour Kasgari et al., 2020). All studies highlight the need of
further investigations in larger clinical trials.Nafamostat and camostat mesilate are inhibitors of
TMPRSS211, a protease fundamental for the penetration of coronaviruses
into the cell (Mascolo et al., 2020). First evidence showed a clinical
improvement with the use of nafamostat and hydroxychloroquine, or
nafamostat and favipiravir in severe COVID-19 patients (Doi et al.,
2020; Iwasaka et al., 2020). Moreover, nafamostat was also effective in
three cases of elderly patients with COVID-19 pneumonia. Both drugs are
currently undervaluation in different clinical trials
(www.clinicaltrials.gov).Ivermectin , a drug used for parasite infestations, has the
ability to reduce, in vitro, the viral RNA of SARS-CoV-2 (Caly et al.,
2020). Today, clinical observational data on the use of this medicine
are conflicting. The ICON study, a chart review of consecutive patients
hospitalized with confirmed COVID-19 treated with or without ivermectin
(200 μg/kg at day 1 and at the discretion of the physician at day 7),
showed a lower mortality in the ivermectin group, but no difference was
found for the extubation rates or length of stay (Rajter et al., 2020).
Another retrospective study conducted in hospitalized patients with
COVID showed that a single dose of ivermectin (200 μg/kg) did not
improve clinical and microbiological outcomes of patients with severe
COVID-19. However, as Authors stated, the drug was given at late stages
of infection (median 12 days after the start of symptoms) and at a
standard single dose that could be lower than the half maximal
inhibitory concentration (IC50) needed for SARS-CoV-2 infection
(Camprubí et al., 2020). Ivermectin is also undervaluation in different
clinical trials (www.clinicaltrials.gov). Preliminary results from a
randomized, controlled, phase 3, clinical trials, evaluating the
recovery from COVID-19, showed the efficacy of the combination
ivermectin and doxycycline compared to placebo (NCT04523831).
Finally, monoclonal antibodies (figure 2), such as meplazumab ,REGN-COV2 , and bamlanivimab , have been developed to
prevent the viral attachment of SARS-CoV-2 to host cells.
Meplazumab is listed among antiviral agents because, based on
its mechanism of action, it can control the virus replication. In fact,
it is an inhibitor of CD147, a glycoprotein involved in the viral entry
of SARS-CoV-2 by interacting with the coronavirus S protein. CD147 also
has a pro-inflammatory activity and regulates cytokine secretion and
leukocytes chemotaxis during viral infections. Preliminary results
showed that meplazumab compared to the control group was associated with
a faster improvement of pneumonia (Bian et al., 2020). Two clinical
trials are ongoing to evaluate the safety and efficacy of meplazumab in
patients with COVID-19 (NCT04275245, NCT04586153).REGN-COV2 is a cocktail of two potent monoclonal antibodies
(casirivimab and imdevimab) targeting the spike protein of SARS-CoV-2.
First descriptive data showed that REGN-COV2 is able to reduce the viral
load and the time to alleviate symptoms in non-hospitalized patients
with COVID-19. Moreover, REGN-COV2 also showed positive trends in
reducing medical visits (Regeneron Pharmaceuticals). Clinical trials are
currently ongoing to evaluate its efficacy and safety for the treatment
(NCT04425629, NCT04426695, NCT04381936) or prevention (NCT04452318) of
COVID-19, and a clinical trial is ongoing to assess its safety,
tolerability, pharmacokinetics, and immunogenicity in healthy adult
volunteers (NCT04519437). On November 21st, 2020 The
U.S. Food and Drug Administration (FDA) granted an emergency
authorization for casirivimab and imdevimab for the treatment of mild to
moderate COVID-19 in adults and paediatric patients (≥ 12 years and
weighing at least 40 Kg) with positive results of direct SARS-CoV-2
viral testing and who are at high risk for progressing to severe
COVID-19. This approval based on data from a clinical trial
demonstrating a reduction of COVID-19-related hospitalization or
emergency room visits within 28 days after treatment in patients at high
risk for disease progression (Food and Drug Administration).Bamlanivimab is a recombinant, human IgG1 monoclonal antibody
(mAb) directed against the spike protein of SARS-CoV-2. Recently, a
Phase 1 study of bamlanivimab in hospitalized patients with COVID-19 was
successfully completed (NCT04411628) (Eli Lilly and Company), and an
interim analysis of an ongoing phase 2 clinical trial in outpatients
with recently diagnosed mild or moderate COVID-19 (BLAZE-1, NCT04427501)
showed that one of three doses of bamlanivimab accelerates the natural
decline in viral load over time (Chen et al., 2020c). Moreover,
bamlanivimab has demonstrated to reduce hospitalizations and symptoms
compared to placebo, with the most pronounced effects observed in
high-risk patients (Chen et al., 2020c). Based on these results, on
November 9th, 2020 bamlanivimab was authorized by the
U.S. FDA, as emergency use, for the treatment of mild to moderate
COVID-19 in adults and paediatric patients (≥ 12 years), who are at high
risk for progressing to severe COVID-19 or hospitalization. Bamlanivimab
is recommended to be administered as soon as possible after a positive
COVID-19 test and within 10 days of symptom onset (Eli Lilly and
Company). Currently, bamlanivimab is being evaluated in a phase 3
clinical trial assessing the prevention of COVID-19 in residents and
staff at long-term care facilities (BLAZE-2, NCT04497987), and in the
National Institutes of Health-led ACTIV-2 study in ambulatory COVID-19
patients (Eli Lilly and Company).
Both bamlanivimab and REGN-COV2 are not authorized for use in
hospitalized patients or in patients requiring oxygen therapy due to
COVID-19 as they resulted most effective when given to a patient shortly
after diagnosis, and in patients who have high viral load or who have
not yet mounted their own immune response.
Other drugs potential therapeutics candidates for COVID-19, not
mentioned above, for which we have less evidence are: azidovudine,
galidesivir, tenofovir, lepidasvir, velpatasvir (Alshaeri and Natto,
2020; Scavone et al., 2020).
In conclusion, the role of antiviral agents for COVID-19 is still being
investigated and the few data available does not allow making any
conclusion. Remdesivir is the only one recommended in Europe for
COVID-19 but it was also recently questioned for efficacy and safety and
it is currently undervaluation by the EMA. Regarding monoclonal
antibodies, such as bamlanivimab, which is indicated in patients at high
risk of hospitalization, a question should be raised: “how to define
who might be at risk of hospitalization, since individuals who go to
hospital are frequently difficult to predict?”. Moreover, the place in
therapy of bamlanivimab and REGN-COV2 is tricky too; it would be
interesting to understand which type of patients would benefit from
these therapies.
Lastly, a new monoclonal antibody is currently under early stage of
development in Italy at the MAD (Monoclonal Antibody Discovery) Lab of
the Fondazione Toscana Life Sciences. This investigational therapy was
obtained starting from convalescent plasma. At this moment, researchers
found that the antibody is able to bind the spike protein and disable
the virus. Thus, this therapy could serve both to prevent and treat
Covid-19 (The Florentine, 2020).