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antibiotics
Article
Efficacy and Safety of Remdesivir over Two Waves of the
SARS-CoV-2 Pandemic
Mariacristina Poliseno 1, * , Crescenzio Gallo 2, Donatella Concetta Cibelli 1, Graziano Antonio Minafra 1,
Irene Francesca Bottalico 1, Serena Rita Bruno 1, Maria Luca D’Errico 1, Laura Montemurro 1, Marianna Rizzo 1,
Lucia Barbera 1, Giacomo Emanuele Custodero 1, Antonella La Marca 1, Donatella Lo Muzio 1, Anna Miucci 1,
Teresa Antonia Santantonio 1and Sergio Lo Caputo 1
Citation: Poliseno, M.; Gallo, C.;
Cibelli, D.C.; Minafra, G.A.; Bottalico,
I.F.; Bruno, S.R.; D’Errico, M.L.;
Montemurro, L.; Rizzo, M.; Barbera,
L.; et al. Efficacy and Safety of
Remdesivir over Two Waves of the
SARS-CoV-2 Pandemic. Antibiotics
2021,10, 1477. https://doi.org/
10.3390/antibiotics10121477
Academic Editor: Masafumi Seki
Received: 8 November 2021
Accepted: 29 November 2021
Published: 1 December 2021
Publisher’s Note: MDPI stays neutral
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Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Foggia,
71122 Foggia, Italy; donatellacibelli@yahoo.it (D.C.C.); grazianominafra@gmail.com (G.A.M.);
ibott4@gmail.com (I.F.B.); serenaritabruno@gmail.com (S.R.B.); m.derrico1990@gmail.com (M.L.D.);
laura.monty91@gmail.com (L.M.); mariannarizzo_@libero.it (M.R.); lucia.barbera@outlook.it (L.B.);
g.custodero88@gmail.com (G.E.C.); antonella89la.marca@gmail.com (A.L.M.); dony79@gmail.com (D.L.M.);
annamiucci91@gmail.com (A.M.); teresa.santantonio@unifg.it (T.A.S.); sergiolocaputo@gmail.com (S.L.C.)
2Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
crescenzio.gallo@unifg.it
*Correspondence: polisenomc@gmail.com; Tel.: +39-3471032012
Abstract:
The aim of this study is to describe the features, the outcomes, and the clinical issues related
to Remdesivir administration of a cohort of 220 patients (pts) with COVID-19 hospitalized throughout
the last two pandemic waves in Italy. One hundred and nine pts were enrolled from 1 September
2020, to 28 February 2021 (Group A) and 111 from 1 March to 30 September 2021 (Group B). Notably,
no differences were reported between the two groups neither in the timing of hospitalization. nor in
the timing of Remdesivir administration from symptoms onset. Remarkably, a higher proportion
of pts with severe COVID-19 was observed in Group B (25% vs. 10%, p< 0.001). At univariate and
multivariate analysis, rather than the timing of Remdesivir administration, age, presence of coexisting
conditions, D-dimers, and O2 flow at admission correlated positively to progression to non-invasive
ventilation, especially for patients in Group B. However, the rate of admission in the Intensive Care
Unit and/or death was comparable in the two groups (7% vs. 4%). Negligible variations in serum
GOT, GPT, GGT, and eGFR levels were detected. A mean reduction in heart rate was noticed within
the first three days of antiviral treatment (p< 0.001). Low rate of ICU admission, high rate of clinical
recovery, and good drug safety were observed in COVID-19 patients treated with Remdesivir during
two diverse pandemic waves.
Keywords: remdesivir; COVID-19 waves; real life-study
1. Introduction
Almost two years after its outbreak in Wuhan in December 2019, the current epidemi-
ological scenario of the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) pandemic
is still serious and is constantly evolving [1].
To date, out of a total population of 60,244,639 [
2
], in Italy, the SARS-CoV-2 epidemic
recorded a total number of 4,774,783 cases and 132,120 deaths according to the latest update
of the ISS [3].
The distribution of Coronavirus Disease-2019 (COVID-19) cases in Italy over the
year 2020 was heterogeneous and significantly influenced by the adoption of collective
and individual restrictive measures which, at first, repressed the significant increase of
COVID-19 cases observed at the beginning of 2020 (first “wave”).
After a partial relief in summer, the second, significant “wave” of viral diffusion was
reported in October 2020, followed by a slight decrease until February 2021, as reported
in Figure 1.
Antibiotics 2021,10, 1477. https://doi.org/10.3390/antibiotics10121477 https://www.mdpi.com/journal/antibiotics
Antibiotics 2021,10, 1477 2 of 16
Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 17
After a partial relief in summer, the second, significant “wave” of viral diffusion was
reported in October 2020, followed by a slight decrease until February 2021, as reported
in Figure 1.
Figure 1. Distribution of COVID-19 cases in Italy between the years 2020 and 2021 (separed by the dotted line). Data are
pdated at 2 November 2021 [4].
By the end of the year 2020, the availability of vaccines, along with the effect of re-
gional public health preventive measures, have contributed to curbing viral diffusion,
smoothing the peak of COVID-19 cases from March to June 2021.
In the meantime, SARS-CoV 2 has continued to change, creating new variants with
the potential to affect the transmission, disease severity, diagnostics, therapeutics, and
natural and vaccine-induced immunity.
As to 8 November 2021, data reported by the Integrated Surveillance System of ISS
from genotypic sequencing performed on 72,064 SARS-CoV-2 positive specimens col-
lected since 28 December, outlined the rise of the predominance of the B.1.617.2 Variant
of Concern (VOC) and relative under-lineages. Notably, the VOC B.1.617.2, which has ac-
counted for the 45.1% of all specimens sequenced during the year 2020, has been detected
in the 91.2% of the specimens collected in the 45 day period from 1 October to 8 November
2021 [5].
Consequently, while the vaccination campaign in Italy is slowly being completed,
approximately 2000 new confirmed cases of SARS-CoV-2 infection and 100 COVID-19
cases requiring hospitalization are still reported daily in the country [3,4].
Besides vaccination, which is capable of reducingthe diffusion of SARS-CoV 2 infec-
tion and decreasing its morbidity and mortality [6], disposing of effective treatments to
manage the earliest phases of COVID-19 among those who get infected could be the win-
ning strategy to use in the next months of the pandemic.
Remdesivir, a prodrug of an adenosine nucleotide analogue, is an antiviral agent
with in vitro broad-spectrum activity against diverse viruses families [7–11]. Thanks to its
good antiviral activity and its overall safety demonstrated against Ebola virus disease in
the wake of the 2014–2016 Ebola outbreak in West Africa [9,10], Remdesivir was initially
considered by the scientific community as a promising “antiviral hope” [12,13].
Today, evidence from clinical trials demonstrate its efficacy in shortening the time to
recovery from COVID-19 [14–17]. Moreover, several in vitro studies [18] have assessed
Remdesivir efficacy in new SARS-CoV-2 variants, highlighting a comparable drug effi-
cacy between early SARS-CoV-2 and variants B.1.1.7 and B.1.351, possibly due to the high
conservation of nsp12 region [19].
Figure 1.
Distribution of COVID-19 cases in Italy between the years 2020 and 2021 (separed by the dotted line). Data are
pdated at 2 November 2021 [4].
By the end of the year 2020, the availability of vaccines, along with the effect of regional
public health preventive measures, have contributed to curbing viral diffusion, smoothing
the peak of COVID-19 cases from March to June 2021.
In the meantime, SARS-CoV-2 has continued to change, creating new variants with the
potential to affect the transmission, disease severity, diagnostics, therapeutics, and natural
and vaccine-induced immunity.
As to 8 November 2021, data reported by the Integrated Surveillance System of ISS
from genotypic sequencing performed on 72,064 SARS-CoV-2 positive specimens collected
since 28 December, outlined the rise of the predominance of the B.1.617.2 Variant of Concern
(VOC) and relative under-lineages. Notably, the VOC B.1.617.2, which has accounted for
the 45.1% of all specimens sequenced during the year 2020, has been detected in the 91.2%
of the specimens collected in the 45 day period from 1 October to 8 November 2021 [5].
Consequently, while the vaccination campaign in Italy is slowly being completed,
approximately 2000 new confirmed cases of SARS-CoV-2 infection and 100 COVID-19 cases
requiring hospitalization are still reported daily in the country [3,4].
Besides vaccination, which is capable of reducingthe diffusion of SARS-CoV-2 infection
and decreasing its morbidity and mortality [
6
], disposing of effective treatments to manage
the earliest phases of COVID-19 among those who get infected could be the winning
strategy to use in the next months of the pandemic.
Remdesivir, a prodrug of an adenosine nucleotide analogue, is an antiviral agent
with
in vitro
broad-spectrum activity against diverse viruses families [
7
–
11
]. Thanks to its
good antiviral activity and its overall safety demonstrated against Ebola virus disease in
the wake of the 2014–2016 Ebola outbreak in West Africa [
9
,
10
], Remdesivir was initially
considered by the scientific community as a promising “antiviral hope” [12,13].
Today, evidence from clinical trials demonstrate its efficacy in shortening the time to
recovery from COVID-19 [
14
–
17
]. Moreover, several
in vitro
studies [
18
] have assessed
Remdesivir efficacy in new SARS-CoV-2 variants, highlighting a comparable drug efficacy
between early SARS-CoV-2 and variants B.1.1.7 and B.1.351, possibly due to the high
conservation of nsp12 region [19].
Based on this evidence, Remdesivir has been approved by the FDA for the treatment
of SARS-CoV-2 pneumonia, onthe condition of being prescribed in patients with recent
infection (inferior to ten days) and low-flow oxygen requirement [20].
Nevertheless, Remdesivir properties of reducing the progression of COVID-19 are still
debated [21].
Antibiotics 2021,10, 1477 3 of 16
Moreover, the choice of whether or not nominate a patient for antiviral treatment
could be difficult in real-life settings, for several reasons.
Among them, unreliable time of symptoms onset obtained from patients’ clinical
history; prolonged time interval from patients’ symptoms onset to hospitalization (which
can be worsened by the lack of hospital bed places in emergency conditions); a growing
number of infections in vaccinated patients not eligible to in-hospital treatment with
monoclonal antibodies due to positive serum anti-spike IgG immunoglobulins;technical
times required for antiviral drug supply, that occasionally can be exceeded by a rapid and
fatal COVID-19 progression.
Up until nowadays, limited data exist regarding the use of Remdesivir in real life
[22–26]
.
Could Remdesivir represent a therapeutic option in the current epidemiological scenario,
considering the scarcity of valid therapeutic alternatives available and the frequent, rapid
evolution of SARS-CoV-2 pneumonia also in patients with mild COVID-19 and recent
symptom onset?
The primary aim of this study is to describe the features, the outcomes, and the clinical
issues related to antiviral administration in a cohort of patients with COVID-19 treated
with Remdesivir.
The secondary aim is to outline possible variations in the efficacy and safety of the an-
tiviral treatment among patients over the last two pandemic waves in Italy, considering the
changes in the virological and epidemiological setting of SARS-CoV-2 infection observed
in the country.
2. Results
2.1. General Characteristics of Study Population
A total of 220 patients, mainly males (139 pts, 63%), mean (SD) age 60 (46–74) years,
were enrolled in the retrospective analysis.
General features of all patients treated with Remdesivir are reported in Table 1.
Table 1. General features of all patients treated with Remdesivir.
Variables Overall
(N = 220)
Mean (±SD) age, years 60 (46–74)
Gender, n (%)
Males
Females
139 (63)
81 (37)
Vaccinated, n (%) 9 (4)
Coexisting dismetabolic conditions, n (%)
Hypertension
Obesity
Type II diabetes
102 (49)
54 (26)
53 (25)
Two or more coexisting conditions, n (%) 70 (39)
Median time (IQR) from symptom onset to
Hospitalization, days 6 (3–8)
Median time (IQR) from symptom onset to
Remdesivir, days 7 (4–9)
Laboratory tests at admission, median (IQR)
RPC, mg/dL
IL-6, pg/mL
D-dimer, ng/mL
GOT, UI/mL
GPT, UI/mL
GGT, UI/mL
eGFR, mL/min
48 (21–108)
17 (7–37)
755 (453–1409)
28 (21–40)
28 (19–40)
37 (23–61)
91 (72–107)
Antibiotics 2021,10, 1477 4 of 16
Table 1. Cont.
Variables Overall
(N = 220)
Oxygen flow required at admission, n (%)
Low flow oxygen
HFNC
NIV
187 (85)
25 (11)
8 (4)
COVID-19 Severity of Disease, n (%)
Mild
Moderate
Severe
Critical
15 (7)
108 (49)
79 (35)
18 (8)
Progression to Non Invasive Ventilation, n (%) 60 (27)
Outcome, n (%)
Intensive Caare Unit Admission/death
Clinical Recovery
23 (10)
197 (89)
Virological Recovery, n (%) 159 (72)
Median time (IQR) from first positive to first
negative SARS-CoV-2 PCR on nasal-pharyngeal
swab, days
20 (12–28)
Median (IQR) duration of hospital stay, days 15 (11–23)
SD: Standard Deviation; IQR: Interquartile Range (Q1 to Q3); CRP: C Reactive Protein; IL-6: Interleukin 6;
GOT: Glutamic Oxaloacetic Transaminase; GPT: Glutamic Piruvic Transaminase; GGT: Gamma Glutammil
Transpeptidase; eGFR: esteemed Glomerular Filtration Rate.
At least one cardio metabolic co existing condition was present in 150 subjects (68%),
especially hypertension (108 pts, 49%). A slight increase of inflammation markers at admis-
sion was reported (median (IQR) C Reactive Protein, CRp = 48
(21–108) mg/dL
, median
(IQR) Interleukin-6, IL-6 = 17 (7–37) ng/mL, median [IQR] D-dimer = 755
(453–1409)) ng/mL
).
Remdesivir was prescribed after a median (IQR) 7 (4–9) days from symptoms on-
set. Notably, 25 pts (11%) were already receiving oxygen support in High Flow Nasal
Cannulas (HFNC) and 8 pts (4%) in non-invasive ventilation (NIV) at the moment of
Remdesivir administration.
After a median (IQR) 15 (11–23) days, clinical recovery was observed in 197 pts (89%),
159 of whom also reported virological recovery after a median (IQR) 20 (12–28) days.
Then, the total population was divided into two distinct groups according to the date
of hospital admission (see Methods section):
•Group A: 109 patients admitted from 1 September 2020 to 28 February 2021;
•Group B: 111 patients admitted from 1 March to 30 September 2021.
As shown in Table 2, no significant differences were observed between Group A
and B in regard to the time of hospitalization from symptom onset (median (IQR) 5 (3–8)
vs. 6 (3–8) days respectively (p= 0.134). The timing of Remdesivir administration from
symptom onset was also comparable: median 7(5–9) in Group A vs. 7 (4–9) days in Group
B respectively (p= 0.453).
Age, gender, the prevalence of coexisting cardio metabolic conditions, and baseline
inflammation markers at admission were also similar in the two groups. Remarkably, a
higher proportion of pts with severe COVID-19 (56 pts, 25% vs. 23 pts, 10%, p< 0.001) and
a higher proportion of patients evolving from low flow oxygen support to NIV (29 pts, 13%
vs. 15 pts, 7%, p= 0.028) was observed in Group B compared to Group A.
Antibiotics 2021,10, 1477 5 of 16
Table 2.
General features of patients admitted from 1 September 2020 to 28 February 2021 (Group A) and patients admitted
from 1 March to 30 September 2021 (Group B). * A p< 0.05 (bold) was considered as statistically significant.
Variables
COVID-19 pValue *
Second Wave
Group A
(N = 109)
Third Wave
Group B
(N = 111)
Mean (±SD) age, years 62 (50–74) 58 (42–74) 0.057
Gender, n (%)
Males 70 (32) 69 (31) 0.781
Females 39 (18) 42 (19)
Vaccinated, n (%) 0 (0) 9 (8) 0.003
Coexisting cardio metabolic conditions, n (%)
Hypertension
Obesity
Type II diabetes
60 (29)
26 (12)
29 (14)
42 (20)
28 (13)
24 (11)
0.004
1.00
0.341
Two or more coexisting conditions, n (%) 38 (34) 32 (28) 0.177
Median time (IQR) from symptom onset to
hospitalization, days 5 (3–8) 6 (3–8) 0.134
Median time (IQR) from symptom onset to
Remdesivir, days 7 (5–9) 7 (4–9) 0.453
Laboratory tests at admission, median (IQR)
RPC, mg/dL
IL-6, pg/mL
D-dimers, ng/mL
GOT, UI/mL
GPT, UI/mL
GGT, UI/mL
eGFR, mL/min
36 (22–108)
17 (8–36)
735 (398–1568)
25 (20–36)
28 (20–42)
47 (23–69)
86 (69–100)
52 (21–107)
16 (7–37)
794 (504–1222)
30 (23–42)
28 (19–40)
34 (23–63)
97 (79–111)
0.547
0.458
0.313
0.014
0.786
0.097
0.006
Oxygen flow required at admission, n (%)
Low flow oxygen 94 (43) 93 (13) 0.032
HFNC 12 (5) 13 (6)
NIV 3 (1) 5 (2)
COVID-19 Severity of disease, n (%)
Mild 8 (4) 7 (3) <0.001
Moderate 68 (31) 40 (18)
Severe 23 (10) 56 (25)
Critical 10 (94 8 (4)
Progression to Non Invasive Ventilation, n (%) 15 (14) 29 (26) 0.028
Outcome, n (%)
Intensive Care Unit admission/Death 15(7) 9 (4) 0.200
Clinical Recovery 94 (42) 102 (46)
Virological Recovery, n (%) 26 (23) 35 (12) 0.203
Median time (IQR) from first positive to first
negative SARS-CoV-2 PCR on
nasal-pharyngeal swab, days
21 (13–35) 19 (12–24) 0.062
Median (IQR) duration of hospital stay, days 16 (11–25) 15 (10–22) 0.412
SD: Standard Deviation; IQR: Interquartile Range (Q1 to Q3); RPC: C Reactive Protein; IL-6: Interleukin 6; GOT: Glutamic Oxaloacetic
Transaminase; GPT: Glutamic Piruvic Transaminase; GGT: Gamma Glutammil Transpeptidase; eGFR: esteemed Glomerular Filtration Rate.
Nevertheless, the rate of patients dead or admitted in ICU were comparable between
patients in Group A and Group B (15 pts, 7% vs. 9 pts, 4%, p= 0.200).
Differences reported in median (IQR) duration of hospital stay (16 (11–25) vs. 15
(10–22) days, p= 0.412) and median (IQR) time to first negative SARS-CoV-2 PCR on
Antibiotics 2021,10, 1477 6 of 16
nasal-pharyngeal swab (21 (13–35) vs. 19 (12–24) days, p= 0.062) was also non-significant
between the two Groups.
2.2. Remdesivir Efficacy
Correlation tests performed for the whole population treated with Remdesivir high-
lighted a significant positive correlation between date of hospitalization (r = 0.219, p= 0.001),
age (r = 0.159, p= 0.020), presence of coexisting conditions (r = 0.199, p= 0.003), elevated
baseline inflammation markers [D-dimer (r = 0.195, p= 0.004, C Reactive Protein (CRP)
r = 0.186, p= 0.006, Inter-leukin 6 (IL-6) r = 0.172, p= 0.014)] high-flow oxygen support
required at admission (r = 0.423, p< 0.001) and progression to non invasive ventilation.
Conversely, a significant negative correlation was outlined between clinical recovery
and age (r =
−
0.192, p= 0.005), presence of coexisting conditions (r =
−
0.233, p= 0.001),
elevated D-dimer (r =
−
0.238, p< 0.0001) and IL-6 (r =
−
0.157, p= 0.025) at admission and
high-flow oxygen support required at baseline (r = −0.268, p= 0.001).
Other correlations are reported in Table 3. Notably, no correlation was observed
between the time of Remdesivir administration from symptom onset and neither of the
variables selected.
Table 3.
Spearman/Pearson’s correlation coefficient matrix between patient’s demographic, clinical and laboratory features
and (i) Progression to non-invasive ventilation (NIV); (ii) Clinical recovery, (iii) Hospital length-of-stay, (iv) Time to
negativization of SARS-CoV-2 PCR on nasal-pharyngeal swab. A p< 0.05 (bold) was considered as statistically significant.
Variables Progression to NIV Clinical
Recovery
Hospital
Length-of Stay Time to Negativization
rprprprp
Age 0.159 0.020 −0.192 0.005 0.291 <0.001 0.125 0.129
Male gender 0.062 0.363 0.045 0.505 0.089 0.167 0.085 0.302
Coexisting conditions 0.199 0.003 −0.233 0.001 0.222 <0.001 0.034 0.682
D-dimer at admission 0.195 0.004 −0.238 <0.001 0.203 0.003 0.091 0.276
CRP at admission 0.186 0.006 −0.127 0.062 0.117 0.087 0.128 0.123
IL-6 at admission 0.172 0.014 −0.157 0.025 0.141 0.045 0.125 0.141
Oxygen support at admission 0.423 <0.001 −0.268 0.001 0.094 0.066 0.115 0.164
Time from onset to hospitalization −0.010 0.885 0.113 0.094 −0.103 0.126 −0.011 0.893
Time from onset to Remdesivir −0.006 0.930 0.019 0.777 −0.036 0.595 0.163 0.048
Date of hospitalization 0.219 0.001 0.040 0.560 0.018 0.791 −0.076 0.357
RPC: C Reactive Protein; IL-6: Interleukin 6; NIV: non invasive ventilation.
A naïve Bayesian Classifier (see Methods section) was modeled for each group of patients.
For both groups, all receiving Remdesivir in association to standard of care, the
independent probability of progression to NIV in accordance to first eight best-ranked
variables identified at univariate analysis among patients’ clinical and laboratory findings
admission, was modeled. Results are graphically reported in Figures 2and 3.
For Group A, the NBC showed that classification accuracy (CA) reached 90.8% and
Area Under Curve (AUC) 0.966 considering patients’ O
2
flow required at baseline, severity
of disease, time of hospitalization from symptom onset and inflammation markers at
admission, modeling a 20% risk of progressing to NIV.
For Group B, a CA 86% and AUC 0.917 were obtained considering patients’ severity
of disease, O
2
flow at baseline, time of hospitalization from symptom onset, age, gender,
and coexisting condition, in particular hypertension and obesity, predicting a 40% risk of
progressing to NIV.
The time of Remdesivir administration was not considered in both models as not significant.
Antibiotics 2021,10, 1477 7 of 16
Antibiotics 2021, 10, x FOR PEER REVIEW 7 of 17
variables identified at univariate analysis among patients’ clinical and laboratory findings
admission, was modeled. Results are graphically reported in Figures 2 and 3.
Figure 2. Probability of progression to non invasive ventilation according to Bayesian classifier
(NBC). Patients treated with Remdesivir hospitalized during the second COVID-19 wave (Septem-
ber 2020–February 2021—Group A).
Figure 2.
Probability of progression to non invasive ventilation according to Bayesian classifier
(NBC). Patients treated with Remdesivir hospitalized during the second COVID-19 wave (September
2020–February 2021—Group A).
Antibiotics 2021, 10, x FOR PEER REVIEW 8 of 17
Figure 3. Probability of progression to non-invasive ventilation according to Bayesian classifier
(NBC). Patients treated with Remdesivir hospitalized during the second COVID-19 wave (March
2021–September 2021—Group B).
For Group A, the NBC showed that classification accuracy (CA) reached 90.8% and
Area Under Curve (AUC) 0.966 considering patients’ O2 flow required at baseline, sever-
ity of disease, time of hospitalization from symptom onset and inflammation markers at
admission, modeling a 20% risk of progressing to NIV.
For Group B, a CA 86% and AUC 0.917 were obtained considering patients’ severity
of disease, O2 flow at baseline, time of hospitalization from symptom onset, age, gender,
and coexisting condition, in particular hypertension and obesity, predicting a 40% risk of
progressing to NIV.
The time of Remdesivir administration was not considered in both models as not
significant.
2.3. Remdesivir Safety
2.3.1. Liver and Kidney Toxicity
The analysis included 205 patients with at least one Glutamic Oxaloacetic Transami-
nase (GOT), Glutamin Piruvic Transaminase (GPT), Gamma Glutammil Transpeptidase
(GGT), and esteemed Glomerular Filtration Rate (Egfr) assessment available at baseline
and within seven days from Remdesivir suspension.
The median (IQR) baseline GOT value detected was 28 (21–40) UI/mL; a decrease to
a median (IQR) value of 22 (17–31) UI/mL (p < 0.001) was observed by the end of the treat-
ment.
Conversely, a slight, non-significant, increase in GGT from a median (IQR) value of
37 (23–61) to 44 (26–74) UI/mL (p = 0.101) was observed, along with a significant increase
(p < 0.001) of GPT serum levels from a median (IQR) baseline value before Remdesivir of
28 (19–40) to a final median value of 37 (22–61) UI/mL after Remdesivir. Notably, the
Figure 3.
Probability of progression to non-invasive ventilation according to Bayesian classifier
(NBC). Patients treated with Remdesivir hospitalized during the second COVID-19 wave (March
2021–September 2021—Group B).
Antibiotics 2021,10, 1477 8 of 16
2.3. Remdesivir Safety
2.3.1. Liver and Kidney Toxicity
The analysis included 205 patients with at least one Glutamic Oxaloacetic Transami-
nase (GOT), Glutamin Piruvic Transaminase (GPT), Gamma Glutammil Transpeptidase
(GGT), and esteemed Glomerular Filtration Rate (Egfr) assessment available at baseline
and within seven days from Remdesivir suspension.
The median (IQR) baseline GOT value detected was 28 (21–40) UI/mL; a decrease
to a median (IQR) value of 22 (17–31) UI/mL (p< 0.001) was observed by the end of
the treatment.
Conversely, a slight, non-significant, increase in GGT from a median (IQR) value of
37 (23–61) to 44 (26–74) UI/mL (p= 0.101) was observed, along with a significant increase
(p< 0.001)
of GPT serum levels from a median (IQR) baseline value before Remdesivir
of 28 (19–40) to a final median value of 37 (22–61) UI/mL after Remdesivir. Notably, the
analysis was repeated on a subset of patients (19 subjects) with altered baseline GPT values
(
≥
2 but
≤
5 times the normal value): mean (SD) baseline value was 112 (33) UI/mL vs. 106
(57) UI/mL reported after Remdesivir administration (p= 0.590).
The median (IQR) baseline eGFR was 91 (72–107) mL/min, which slightly increased to
a median (IQR) of 100 (83–114) mL/min (p< 0.001). Furthermore, in this case, the analysis
was repeated on a subset of 28 subjects in which Remdesivir was administered with eGFR
values >30 mL/min but <60 mL/min. Mean reported baseline value was 47 mL/min;
mean reported eGFR value after Remdesivir was 65 mL/min (p= 0.002).
2.3.2. Heart Safety and Cardiac Rhythm Abnormalities
There were 133 patients included in the study of Remdesivir heart safety, as they un-
derwent heart rhythm monitoring through serial Electrocardiograms (ECGs) (see Methods
section). They were mainly males (83 pts, 63%), mean age 60 (57–73) years, and already
presented cardiovascular comorbidities, such as chronic atrial fibrillation (17 pts, 32%),
history of acute myocardial infarction (14 pts, 11%), history of chronic heart disease (14 pts,
11%). Notably, 55 pts (42%) presented with severe COVID-19.
Compared to baseline, over a median (IQR) of 6 (6–7) ECGs performed in the course of
hospitalization, a significant reduction of heart rate to a minimum of 36 bpm was observed
after administration of Remdesivir (Kruskal-Wallis p< 0.0001) from mean (SD) 84 (17) bpm
at admission to 62 (13) bpm at discharge. The heart rate reduction was more significant
from day 1 to day 3 of antiviral administration (Kruskal-Wallis p< 0.001) than from day 3
to day 5 (Kruskal-Wallis p< 0.05), as shown in Figure 4.
The median (IQR) heart rate reduction observed was 22 (14–34) bpm. Heart rate re-
duction was proportional to baseline heart rate values (r = 0.784, p< 0.001), age (
r = −0.230
,
p= 0.008
), presence of arterial hypertension (r =
−
0.203, p= 0.02). In 70 pts (53%) prolon-
gation of QTc interval > 440 ms in women and >460 ms in men was reported. New-onset
heart rhythm abnormalities were noticed in 13 pts (10%). six cases of atrial fibrillation and
seven cases of isolated supraventricular extrasystoles were documented.
In any case, the occurrence of clinical symptoms related to bradycardia, to other
cardiac rhythm abnormalities, or to QTc prolongation implied Remdesivir discontinuation.
Antibiotics 2021,10, 1477 9 of 16
Antibiotics 2021, 10, x FOR PEER REVIEW 9 of 17
analysis was repeated on a subset of patients (19 subjects) with altered baseline GPT val-
ues (≥2 but ≤5 times the normal value): mean (SD) baseline value was 112 (33) UI/mL vs.
106 (57) UI/mL reported after Remdesivir administration (p= 0.590).
The median (IQR) baseline eGFR was 91 (72–107) mL/min, which slightly increased
to a median (IQR) of 100 (83–114) mL/min (p < 0.001). Furthermore, in this case, the anal-
ysis was repeated on a subset of 28 subjects in which Remdesivir was administered with
eGFR values >30 mL/min but <60 mL/min. Mean reported baseline value was 47 mL/min;
mean reported eGFR value after Remdesivir was 65 mL/min (p = 0.002).
2.3.2. Heart Safety and Cardiac Rhythm Abnormalities
There were 133 patients included in the study of Remdesivir heart safety, as they
underwent heart rhythm monitoring through serial Electrocardiograms (ECGs) (see Meth-
ods section). They were mainly males (83 pts, 63%), mean age 60 (57–73) years, and already
presented cardiovascular comorbidities, such as chronic atrial fibrillation (17 pts, 32%),
history of acute myocardial infarction (14 pts, 11%), history of chronic heart disease (14
pts, 11%). Notably, 55 pts (42%) presented with severe COVID-19.
Compared to baseline, over a median (IQR) of 6 (6–7) ECGs performed in the course
of hospitalization, a significant reduction of heart rate to a minimum of 36 bpm was ob-
served after administration of Remdesivir (Kruskal-Wallis p < 0.0001) from mean (SD) 84
(17) bpm at admission to 62 (13) bpm at discharge. The heart rate reduction was more
significant from day 1 to day 3 of antiviral administration (Kruskal-Wallis p < 0.001) than
from day 3 to day 5 (Kruskal-Wallis p < 0.05), as shown in Figure 4.
Figure 4. Box plot showing heart rate changes in course of Remdesivir administration on a subset
of 133 patients.* p < 0.05; **** p < 0.001.
The median (IQR) heart rate reduction observed was 22 (14–34) bpm. Heart rate re-
duction was proportional to baseline heart rate values (r = 0.784, p < 0.001), age (r = −0.230,
p = 0.008), presence of arterial hypertension (r = −0.203, p = 0.02). In 70 pts (53%) prolonga-
tion of QTc interval > 440 ms in women and >460 ms in men was reported. New-onset
heart rhythm abnormalities were noticed in 13 pts (10%). six cases of atrial fibrillation and
seven cases of isolated supraventricular extrasystoles were documented.
In any case, the occurrence of clinical symptoms related to bradycardia, to other car-
diac rhythm abnormalities, or to QTc prolongation implied Remdesivir discontinuation.
Figure 4.
Box plot showing heart rate changes in course of Remdesivir administration on a subset of
133 patients.* p< 0.05; **** p< 0.001.
3. Discussion
Remdesivir is a pro-drug of an adenosine nucleoside triphosphate analog [
27
]. After
being converted in its active form, Remdesivir interferes with the action of viral RNA-
dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN),
causing a decrease in viral RNA production [28,29].
In some viruses, such as the respiratory syncytial virus, Remdesivir causes the RNA-
dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce
an irreversible chain termination. Unlike with many other chain terminators, this is not
mediated by preventing the addition of the immediately subsequent nucleotide but is
instead delayed, occurring after five additional bases have been added to the growing RNA
chain [
30
]. Hence, Remdesivir is classified as a direct-acting antiviral agent that works as a
delayed chain terminator.
Data from worldwide clinical trials have concluded that the five-day course treatment
with Remdesivir is effective in reducing time to recovery and duration of hospital stay
in patients with moderate to severe SARS-CoV-2 pneumonia requiring low flow oxygen
support [14–17].
Moreover, Remdesivir efficacy in reducing both SARS-CoV-2 viral RNA and subge-
nomic RNA has been demonstrated both in vitro and in vivo [31,32].
Remdesivir is currently approved in Italy to treat patients hospitalized with SARS-CoV-
2 pneumonia having recent symptom onset and requiring low-flow oxygen ventilation [
20
].
Nevertheless, interim results from the Solidarity Trial of 11,330 patients randomized to
receive four repurposed antiviral drugs—remdesivir, hydroxychloroquine, lopinavir, and
interferon beta-, show no effect of Remdesivir (administered in 2750 subjects) on mortality,
initiation of ventilation, or duration of hospital stay, neither in patients with low oxygen
requirement [21].
The enrollment of patients with COVID-19 of diverse stages and severity [
14
], the
absence of a standardized method of measure of Remdesivir efficacy [
15
–
17
], and, in
some trials, the absence of a Remdesivir-free control arm [
15
], could partially explain the
controversial results of clinical trials, that should also be re-interpreted on the basis of what
we have learned about the complex and rapid evolution of the natural course of COVID-19
from clinical practice.
Antibiotics 2021,10, 1477 10 of 16
Recent real-life studies support the use of Remdesivir as related to a reduction in mor-
tality rate compared to placebo [
23
,
25
,
26
] and associated with a good safety profile
[23,26]
.
This is the first report, in Italy, of Remdesivir use in patients hospitalized in the course
of the year 2021.
The scenario of the SARS-CoV-2 pandemic in Italy has enormously changed in the
course of the last year, due to the beginning and the progression of the vaccination cam-
paign, the availability of new post-exposure treatments as monoclonal antibodies, and,
lastly, because of the emergence of new SARS-CoV-2 variants with recognized increased
transmissibility and pathogenicity, enhanced ability to evade detection by diagnostic tests,
decreased susceptibility to therapeutic agents (i.e., monoclonal antibodies) and good capac-
ity to escape natural or vaccine-induced immunity [33,34].
In our observation, patients treated with Remdesivir from March to September 2021,
were slightly younger and substantially similar in regard to clinical and laboratory features
at admission to subjects observed during the first five months of the study.
Fortunately, a negligible proportion of vaccinated subjects with COVID-19 was admit-
ted over the year 2021. Nevertheless, a higher number of severe forms of COVID-19 disease
and, consequently, a significant propensity towards a respiratory worsening requiring non
invasive ventilation were observed among this group of patients.
It is worth mentioning that patients in both groups were hospitalized and received
Remdesivir after approximatively one week from symptom onset.
Both the difficulties in defining the precise symptom onset from patients stories and
the common wait-and-see-attitude of General Practitioners contribute to (i) causing a bias
in the calculation of the precise time of symptom onset and (ii) producing a delay in the
timing of hospital admission from the onset of the infection. The latter condition, in partic-
ular, could explain the correlation observed between baseline oxygen flow requirement
and the progression towards non-invasive ventilation, which can be also influenced by
different timing and doses of steroid treatments prescribed at home, not included in our
data collection.
The importance of identifying a rapid strategy to contrast COVID-19 progression, (i.e.,
post-exposure prophylaxis with monoclonal antibodies or early start of antiviral treatment)
is clearly highlighted by our analysis.
Following what was already reported in the literature [
35
], our data have confirmed
that the presence of pre-existing comorbidities and the elevation of baseline inflammation
marker have a great impact on the progression of COVID-19. This data suggest that the
careful observation of patients at admission and their frequent re-evaluation in the course
of hospitalization is essential for choosing the proper treatment accordingly to individual
characteristics and COVID-19 severity and progression.
Nevertheless, despite the higher clinical complexity of patients hospitalized in recent
times, in our experience a good recovery rate and a very small proportion of patients
admitted in Intensive Care Unit or dead over the total population was observed, suggesting
that the antiviral treatment has been an efficacious strategy regardless from the date of
patients’ admission.
We investigated Remdesivir cardiac, renal, and hepatic safety.
Due to its real life-design, our study allowed us to observe the effects of a five-day
course treatment with Remdesivir in patients with mild renal and hepatic impairment at
admission. A negligible variation in glomerular filtration rate and liver enzymes, more
related to the evolution of the viral infection than to drug-related toxicity, was reported.
Moreover, despite a significant reduction in heart rate observed after Remdesivir adminis-
tration, no serious cardiovascular toxicity was observed in patients with COVID-19, even
in those with severe disease and cardiovascular comorbidities.
Our study has some limitations.
The first is its monocentric design: as a consequence, results might be affected by local
practice in the management of COVID-19. Secondly, its retrospective nature, that did not
Antibiotics 2021,10, 1477 11 of 16
allow to include all subjects in the analysis of renal and hepatic safety and in the study of
heart rate abnormalities, due to the lack of blood samples and ECGs.
Lastly, we are aware that the absence of a Remdesivir-free control group could affect
the completeness and the reliability of the results, which should therefore be interpreted
cautiously also because the study was not conducted with randomized groups that could
limit the presence of confounding factors.
Nevertheless, this report provides several insights from clinical practice and tries,
for the first time, to define the utility of antiviral treatment in the context of two diverse
pandemic waves.
4. Materials and Methods
4.1. Data Collection
All patients hospitalized in the COVID-19 Infectious Diseases Unit in Foggia Univer-
sity Hospital from September 1, 2020 to September 30, 2021 were retrospectively included
in the analysis at the condition of meeting the following criteria: (i) age
≥
18 years; (ii) diag-
nosis of SARS-CoV-2 infection confirmed with positive Polymerase Chain Reaction (PCR)
on nasal-pharyngeal swab; (iii five-day course treatment with Remdesivir.
After anamnesis and clinical evaluation, Remdesivir was prescribed in patients with
recent symptom onset (inferior to ten days), radiological evidence of SARS-CoV-2 pneu-
monia, and low flow Oxygen requirement, according to international guidelines and the
Italian Agency of Drug indications [36,37].
It must be mentioned that, in a limited number of cases, patients requiring oxygen
support from HFNCNIV were considered eligible to treatment with Remdesivir upon
clinician’s judgement on a case-by-case basis, independently from the purpose of this study.
However, the time criterion (symptom onset inferior to ten days) was fulfilled in all cases.
Besides antiviral treatment, all patients received standard of care therapy for SARS-CoV-
2 pneumonia: Dexamethasone 6 mg once daily, Low Molecular Weight Heparin (LMWH)
80 mg/kg once daily or 100 mg/kg twice daily according to clinical evidence of acute
pulmonary embolism and/or specific cardiac conditions, antimicrobial prophylaxis with
Ceftriaxone 2 gr or Levofloxacin 750 mg once daily.
Eligibility to Remdesivir was established at admission and the drug was requested
upon nominal demand to the Italian Agency of Drugs and delivered by hospital pharmacy
within approximatively 48 h. Contraindications included (i) GPT
≥
5 times the normal
range values (40 UI/mL), (ii) eGFR < 30 mL/min, hemodialysis, or peritoneal dialysis,
(iii) evidence of severe bradycardia (heart rate < 55 bpm, or <65 bpm in presence of
symptoms) at ECG performed at admission.
Once provided, antiviral treatment was started and continued regardless of a potential
worsening in clinical conditions.
Conversely, increase in GPT
≥
5 times the normal range values, decrease of eGFR
below 30 mL/min, evidence of symptomatic bradycardia (the association of a heart rate
<60 bpm and the development of clinical manifestations of syncope or presyncope, transient
dizziness, or light-headedness, heart failure symptoms, or confusedstates), represented
reasons for antiviral discontinuation.
No treatment interruption for any cause was recorded.
All patients received a blood test including dosage of D-dimers, IL-6, CRP, GOT, GPT,
GGT serum levels, eGFR at baseline, during and after Remdesivir administration according
to clinical necessities.
All patients had one ECG recorded at admission and discharge.
Starting from February 2021, due to asymptomatic sinus bradycardia during Remde-
sivir administration in a subset of patients of the same cohort [
38
], daily ECGs in the course
or immediately after Remdesivir administration were scheduled for all patients.
Data regarding heart rate and related new-onset abnormalities, liver and kidney
function monitoring were reported in the case report form.
Antibiotics 2021,10, 1477 12 of 16
Demographics, clinical data, and data regarding COVID-19 medical history (vaccina-
tion, data of first positive and first negative SARS-CoV-2 PCR, date of hospital admission
and discharge, date of Remdesivir administration, co-medications, oxygen support re-
quired at admission) were retrieved from medical charts.
The timing of hospitalization from symptom onset and timing of Remdesivir adminis-
tration from symptoms onset were calculated, along with the duration of hospital length of
stay and time to first negative SARS-CoV-2 PCR on a nasal-pharyngeal swab.
The patient’s outcome and severity of disease were established after discharge or
transfer to the Intensive Care Unit.
We defined “Clinical recovery” as the stable remission of both symptoms and signs of
infection recorded at the patient presentation, along with (i) a stable reduction CRP to a
value <10 mg/L and (ii) a peripheral oxygen blood saturation >95% in room air.
Nasal-pharyngeal swabs were routinely performed after the suspension of Oxygen
therapy. At the condition that clinical recovery was achieved, negative SARS-CoV2 PCR
on nasal-pharyngeal swabs was preferred, but not mandatory, to allow patients discharge.
We defined “Virological recovery” as the association of clinical recovery and negative
SARS-CoV-2 PCR on nasal pharyngeal swab performed before discharge.
The severity of disease was defined in accordance with current WHO indications [
39
].
4.2. Study Design and Statistical Analysis
Figure 5shows the design of our research, which was essentially double aimed:
•
A primary endpoint was to report on the efficacyof the five days course treatment
with Remdesivir.
Antibiotics 2021, 10, x FOR PEER REVIEW 13 of 17
4.2. Study Design and Statistical Analysis
Figure 5 shows the design of our research, which was essentially double aimed:
Figure 5. Flow-chart illustrating study design.
• A primary endpoint was to report on the efficacyof the five days course treatment
with Remdesivir.
To this aim, a descriptive statistic of clinical characteristics and outcomes, oxygen
support, and laboratory markers at baseline of all patients treated with Remdesivir in our
Unit in the study period was performed. Categorical variables are reported in terms of
absolute number and percentages; continuous variables are described as means (Standard
Deviation, SD) or medians (Inter Quartile Range, IQR, QI to Q3) according to their para-
metric or non-parametric distributions.
Over the course of the study period, covering all year 2021, a significant change in
clinical and epidemiological features of new SARS-CoV 2 infections was observed in Italy,
due to the rise in the prevalence of SARS-CoV-2 VOC, the increase in the number of new
infections in vaccinated subjects [5] and the availability of new treatments for hospitalized
patients with mild/moderate COVID-19 [40].
In light of these considerations, we aimed to outline if variation in the efficacy and
the safety of the antiviral treatment were observed in course of the year 2021.
To this aim, patients were split, according to the date of hospitalization into two dis-
tinct groups mirroring the two last “pandemic waves” observed in Italian country be-
tween the end of the year 2020 and the year 2021:
- Group A: patients admitted from 1 September 2020 to 28 February 2021;
- Group B: patients admitted from 1 March to 30 September 2021.
Descriptive statistics were performed for each group. The Chi-square test or Fisher
exact test were performed, as appropriate, to compare proportions between Group A and
B. Independent samples Student’s t-test or Mann–Whitney U-test were used, as appropri-
ate, to compare mean/median values. A p < 0.05 was considered statistically significant.
Univariate Analysis (Pearson’s or Spearman’s coefficient calculation as appropriate)
was performed for the total population to highlight possible correlation between: (i) Pro-
gression to non-invasive ventilation; (ii) Clinical Recovery; (iii) Hospital length-of-stay;
(iv) Time from first positive to first negative nasal-pharyngeal swab and patients
Figure 5. Flow-chart illustrating study design.
To this aim, a descriptive statistic of clinical characteristics and outcomes, oxygen
support, and laboratory markers at baseline of all patients treated with Remdesivir in
our Unit in the study period was performed. Categorical variables are reported in terms
of absolute number and percentages; continuous variables are described as means (Stan-
dard Deviation, SD) or medians (Inter Quartile Range, IQR, QI to Q3) according to their
parametric or non-parametric distributions.
Over the course of the study period, covering all year 2021, a significant change in
clinical and epidemiological features of new SARS-CoV-2 infections was observed in Italy,
Antibiotics 2021,10, 1477 13 of 16
due to the rise in the prevalence of SARS-CoV-2 VOC, the increase in the number of new
infections in vaccinated subjects [
5
] and the availability of new treatments for hospitalized
patients with mild/moderate COVID-19 [40].
In light of these considerations, we aimed to outline if variation in the efficacy and the
safety of the antiviral treatment were observed in course of the year 2021.
To this aim, patients were split, according to the date of hospitalization into two
distinct groups mirroring the two last “pandemic waves” observed in Italian country
between the end of the year 2020 and the year 2021:
- Group A: patients admitted from 1 September 2020 to 28 February 2021;
- Group B: patients admitted from 1 March to 30 September 2021.
Descriptive statistics were performed for each group. The Chi-square test or Fisher
exact test were performed, as appropriate, to compare proportions between Group A and B.
Independent samples Student’s t-test or Mann–Whitney U-test were used, as appropriate,
to compare mean/median values. A p< 0.05 was considered statistically significant.
Univariate Analysis (Pearson’s or Spearman’s coefficient calculation as appropriate)
was performed for the total population to highlight possible correlation between: (i) Pro-
gression to non-invasive ventilation; (ii) Clinical Recovery; (iii) Hospital length-of-stay;
(iv) Time from first positive to first negative nasal-pharyngeal swab and patients laboratory
and clinical features at baseline, with special focus on the date of hospitalization, the
timing of hospitalization from symptom onset and the timing of Remdesivir administration
from symptom onset. A p< 0.05 was considered statistically significant. Statistics were
performed using Jamovi 1.8.4 package.
Multivariate analysis was performed to identify possible predictors of respiratory
worsening and progression to non invasive ventilation.
Orange 3.30.1 package was used to construct a naïve Bayesian classifier model (NBC).
In a Bayes classifier, the learning agent builds a probabilistic model of the imputed attributes
and uses that model to predict the classification of a selected outcome. In the case of
NBC, the independence assumption is made that the input attributes are conditionally
independent of each other given the classification [41].
In this study, the NBC was used to model the probability of NIV requirement in
accordance with the eight best-ranked variables identified among patients’ clinical and
laboratory findings admission. Two distinct NBCs were modeled with attributes of patients
in Group A and patients in Group B.
A “leave-one-out” validation was used to compute the classification accuracy, sen-
sitivity, and specificity of the models, and to assess them through Area Under the ROC
curve. Results were graphically reported in two distinct nomograms.
•A secondary endpoint of our work was to describe the safety of Remdesivir in terms
of drug-induced liver and kidney toxicity and cardiac rhythm abnormalities.
To this end, all patients with serum GOT, GPT, GGT, and eGFR levels available
at baseline and within seven days from Remdesivir suspension were enrolled in the
analysis. The paired-samples Student’s t-test or Wilcoxon Rank were performed to compare
transaminase and glomerular filtration rate before and after Remdesivir administration,
according to their parametric and non-parametric distribution of the variables. The tests
were repeated on a subset of subjects with GOT and GPT levels at admission
≥
2 but
≤
5 times the normal range and on a subgroup of patients with eGFR values
≥
30 mL/min
but ≤60 mL/min.
Ap< 0.05 was considered statistically significant.
The study of cardiac rhythm was performed on a subset of subjects with at least three
ECGs available recorded in course of Remdesivir, besides those performed at admission
and discharge.
For ECG, the corrected duration of QT interval (QTc) was calculated in relation to
heart rate according to Bazett’s formula [
42
]. QTc prolongation was defined as the detection
of values above the normal range (440 ms for men, 460 ms for women) [
43
]).Possible pre-
Antibiotics 2021,10, 1477 14 of 16
sentation of cardiac arrhythmias related to bradycardia, including sinus pause, sinus node
arrest, tachycardia-bradycardia, atrioventricular block, atrial flutter, atrial fibrillation [44],
and their possible associated clinical complication were also recorded.
Descriptive statistics were performed. Repeated measures were compared withthe
non-parametric ANOVA test. (Kruskal Wallis). A p< 0.05 was considered statistically
significant. Statistics were performed using Jamovi 1.8.4. and GraphPad Prism 9 packages.
5. Conclusions
Low rate of ICU admission and/or death and high rate of clinical recovery were
observed in our cohort of COVID-19 patients treated with Remdesivir throughout the last
two pandemic waves reported in Italy. Notably, higher severity of disease and enhanced
probability of progression to non-invasive ventilation was observed in patients hospitalized
from March to September 2021. Nevertheless, favorable outcomes were observed in a high
proportion of subjects, independently from the date of hospitalization.
Further studies are needed to assess the real advantages of the use of Remdesivir in
the current epidemiological scenario and understand to which extent antiviral treatments
could be properly used to optimize the management of patients with COVID-19.
Author Contributions:
Conceptualization, M.P. and S.L.C.; methodology, M.P. and S.L.C.; soft-
ware, C.G.; validation, C.G.; formal analysis, C.G. and M.P.; investigation, M.P., D.C.C., G.A.M.,
I.F.B., S.R.B. and M.L.D.; resources, M.P., D.C.C. and L.M.; data curation, M.P., L.M., M.R., L.B.,
G.E.C., A.L.M., D.L.M. and A.M.; writing—original draft preparation, M.P.; writing revision and
editing—M.P. and S.L.C.; visualization, M.P.; supervision, S.L.C. and T.A.S.; project administration,
M.P. and S.L.C.; funding acquisition, S.L.C. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
This research study was conducted retrospectively from
data obtained for clinical purposes. The Ethical Committee of Policlinico Riuniti of Foggia was
consulted for ethical approval, that was waived for this research in reason of its retrospective nature,
in accordance to the Italian law. In any case, data of all patients were recorded anonymously and
managed following the Italian requirements regarding the privacy protections and in accordance
withthe 1964 Helsinki declaration (and its amendments).
Informed Consent Statement:
Written informed consent has been obtained from the patients to
publish this paper.
Conflicts of Interest: The authors declare no conflict of interest.
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